Dual action antibiotics

ABSTRACT

The present invention relates to compounds of the Formula (I) that are useful antimicrobial agents and effective against a variety of multi-drug resistant bacteria.

The present invention describes new compounds in which thepharmacophores of quinolone and oxazolidinone are chemically linkedtogether through a linker that is stable under physiological conditionsand a pharmaceutical antibacterial composition containing thesecompounds. These dual action compounds are useful antimicrobial agentseffective against a variety of human and veterinary pathogens includingGram positive aerobic bacteria such as multiply-resistant staphylococci,streptococci and enterococci as well as Gram negative bacteria such asMoraxella catarrhalis and Haemophilus influenza and anaerobic organismssuch as bacteroides spp. and Clostridia spp. species and acid-fastorganism such as Mycobacterium tuberculosis, Mycobacterium avium spp.

The intensive use of antibiotics has exerted a selective evolutionarypressure on microorganisms to produce genetically based resistancemechanisms. Modern medicine and socioeconomic behavior exacerbates theproblem of resistance development by creating slow growth situations forpathogenic microbes, e.g. artificial joints-related infections, and bysupporting long-term host reservoirs, e.g. in immunocompromisedpatients.

In hospital settings, an increasing number of strains of Staphylococcusaureus, Streptococcus pneumoniae, Enterococcus sp., and Pseudomonasaeruginosa, major sources of infections, are becoming multi-drugresistant and therefore difficult if not impossible to treat:

-   -   S. aureus is β-lactam, quinolone and now even vancomycin        resistant.    -   S. pneumoniae is becoming resistant to penicillin and even to        new macrolides.    -   Enteroccocci are quinolone and vancomycin resistant and        β-lactams were never efficacious against these strains. The only        alternative is to use oxazolidinones but these compounds are not        bactericidal and the safety margin is rather low. Further, even        with these drugs, resistance already appears in clinical        practice.

In addition, microorganisms that are causing persistent infections areincreasingly being recognized as causative agents or cofactors of severechronic diseases like peptic ulcers or heart diseases.

The present invention provides new compounds of Formula (I) that areuseful antimicrobial agents and effective against a variety ofmulti-drug resistant bacteria:

-   -   wherein    -   A is a direct bond, a NH, O, S, SO, SO₂, SO₂NH, PO₄, —NH—CO—NH—,        —CO—NH—, —CO—, —CO—O—, —NH—CO—O—, an alkylen group, an alkenylen        group, an alkinylen group, a heteroalkylen group, an arylen        group, a heteroarylen group, a cycloalkylen group, a        heterocycloalkylen group, an alkylarylen group or a        heteroarylalkylen group or a combination of two or more of these        atoms or groups;    -   X is CR5 or N;    -   Y is CR6 or N;    -   U is F or Cl;    -   n is 0, 1, 2 or 3;    -   R1 is H, F, Cl, Br, I, OH, NH₂, an alkyl group or a heteroalkyl        group;    -   R2 is H, F or Cl;    -   R3 is H, an alkyl group, an alkenyl group, an alkinyl group, a        heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group,        an aryl group, a heteroaryl group, an alkylaryl group or a        heteroarylalkyl group; all of which may be substituted with one,        two or more halogen atoms like F or Cl.    -   R4 is a heteroalkyl group, a cycloalkyl group, a        heterocycloalkyl group, an aryl group, a heteroaryl group, an        alkylaryl group or a heteroarylalkyl group;    -   R5 is H, F, Cl, OH, NH₂, an alkyl group or a heteroalkyl group,        or    -   R3 and R5 can be linked via an alkylen, an alkenylen or a        heteroalkylen group or be a part of a cycloalkylen or        heterocyclo-alkylen group; in case R3 is no H and R5 is no H, F,        OH, NH₂ or Cl;    -   R6 is H, F, Cl or OMe;    -   or a pharmacologically acceptable salt, solvate, hydrate or        formulation thereof.

It should be appreciated that certain compounds of formula (I) may havetautomeric forms from which only one might be specifically mentioned ordepicted in the following description, different geometrical isomers(which are usually denoted as cis/trans isomers or more generally as (E)and (Z) isomers) or different optical isomers as a result of one or morechiral carbon atoms (which are usually nomenclatured under theCahn-Ingold-Prelog or R/S system). Further, some compounds may displaypolymorphism. All these tautomeric forms, geometrical or optical isomers(as well as racemates and diastereomers) and polymorphous forms areincluded in the invention.

The term alkyl refers to a saturated or unsaturated (i.e. alkenyl andalkinyl) straight or branched chain alkyl group, containing from one toten, preferably one to six carbon atoms for example methyl, ethyl,propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,iso-pentyl n-hexyl, 2,2-dimethylbutyl, n-octyl; ethenyl (vinyl),propenyl (allyl), iso-propenyl, n-pentyl, butenyl, isoprenyl orhexa-2-enyl; ethinyl, propinyl or butinyl groups. Any alkyl group asdefined herein may be substituted with one, two or more substituents,for example F, Cl, Br, I, NH₂, OH, SH or NO₂.

The terms alkenyl and alkinyl refer to a unsaturated straight orbranched chain alkyl group (having one, two or more double and/or triplebonds, an alkenyl preferably having one or two double bonds and analkinyl preferably having one or two triple bonds), containing from oneto ten, preferably one to six carbon atoms for example: ethenyl (vinyl),propenyl (allyl), iso-propenyl, n-pentenyl, butenyl, isoprenyl orhexa-2-enyl; ethinyl, propinyl or butinyl groups. Any alkenyl or alkinylgroup as defined herein may be substituted with one, two or moresubstituents, for example F, Cl, Br, I, NH₂, OH, SH or NO₂.

The term heteroalkyl refers to an alkyl group as defined herein whereone or more carbon atoms are replaced by an oxygen, nitrogen,phosphorous or sulphur atom for example an alkoxy group such as methoxy,ethoxy, propoxy, iso-propoxy, butoxy or tert.-butoxy, an alkoxyalkylgroup such as methoxymethyl, ethoxymethyl, 1-methoxyethyl,1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, an alkylamino group suchas methylamino, ethylamino, propylamino, isopropylamino, dimethylaminoor diethylamino, an alkylthio group such as methylthio, ethylthio orisopropylthio or a cyano group. It may also refer to one of the abovegroups containing a keto group. The term heteroalkyl furthermore refersto a group derived from a carboxylic acid or carboxylic acid amide suchas acetyl, propionyl, acetyloxy, propionyloxy, acetylamino orpropionylamino, a carboxyalkyl group such as carboxymethyl, carboxyethylor carboxypropyl, a carboxyalkyl ester, an alkylthiocarboxyamino group,an alkoxyimino group, an alkylaminothiocarboxyamino group or analkoxycarbonylamino group. Any heteroalkyl group as defined herein maybe substituted with one, two or more substituents, for example F, Cl,Br, I, NH₂, OH, SH or NO₂.

The term cycloalkyl refers to a saturated or partially unsaturated(having one, two or more double and/or triple bonds), cyclic group withone, two or more rings, having three to 14 carbon ring-atoms, preferablyfrom five or six to ten carbon ring-atoms, for example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, tetralin, cyclopentenyl orcyclohex-2-enyl-groups. Any cycloalkyl group as defined herein may besubstituted with one, two or more substituents, for example F, Cl, Br,I, OH, NH₂, SH, N₃, NO₂, alkyl groups such as methyl or ethyl,heteroalkyl groups such as methoxy, methylamino, dimethylamino orcyanide.

The term heterocycloalkyl refers to a cycloalkyl group as defined hereinwhere one, two or more carbon ring-atoms are replaced by one, two ormore oxygen, nitrogen, phosphorous or sulphur atoms or S(O)₁₋₂ groupsfor example piperidino, morpholino or piperazino groups.

The term aryl refers to an aromatic cyclic group with one, two or morerings, having five to 14 carbon ring-atoms preferably from five or sixto ten carbon ring-atoms, for example phenyl or naphthyl groups. Anyaryl group as defined herein may be substituted with one, two or moresubstituents, for example F, Cl, Br, I, OH, NH₂, SH, N₃, NO₂, alkylgroups such as methyl or ethyl, heteroalkyl groups such as methoxy,methylamino, dimethylamino or cyanide.

The term heteroaryl refers to an aryl group as defined herein where one,two or more ring-carbon atoms are replaced by an oxygen, nitrogen,boron, phosphorous or sulphur atom, for example pyridyl, imidazolyl,pyrazolyl, quinolinyl, isoquinolinyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl andpyridazinyl groups.

The terms arylalkyl, alkylaryl and heteroarylalkyl, heteroalkylarylrefer to groups that comprise both aryl or, respectively, heteroaryl aswell as alkyl and/or heteroalkyl and/or cycloalkyl and/orheterocycloalkyl groups.

Preferred and/or advantageous embodiments of the invention aresubject-matter of the subclaims.

Preferred are compounds of Formula (I), wherein R1 is H or NH₂.

Further preferred are compounds of Formula (I), wherein R2 is H or F.

Moreover preferred are compounds of Formula (I), wherein R3 is an ethyl,a 2-propyl, a C3-C6 cycloalkyl, a phenyl or a pyridyl group. All thesegroups may be substituted by one, two or more fluorine atoms or aminogroups.

Moreover preferred are compounds of Formula (I), wherein R3 is acyclopropyl group.

Further preferred are compounds of Formula (I), wherein R3 and R5together form a bridge of the formula —O—CH₂—N(Me)- or —O—CH₂—CH(Me)-.Herein, the preferred stereochemistry at the chiral center is the onegiving the S configuration in the final compound.

Further preferred are compounds of Formula (I), wherein R4 is a group ofthe formula —NHCOCH═CHAryl, —OHeteroaryl (especially-oxa-3-oxazol),—NHSO₂Me, —NHCOOMe, NHCS₂Me, NHCSNH₂, —NHCSOMe or —NHCOMe.

Especially preferred are compounds of Formula (I), wherein R4 is anacetylamino group.

Moreover preferred are compounds of Formula (I), wherein R5 is H, F, Clor a methoxy group which may be substituted by one, two or threefluorine atoms.

Further preferred are compounds of formula (I), wherein X is N or CH.

Further preferred are compounds of Formula (I), wherein Y is N or CF.

Further preferred are compounds of Formula (I), wherein n is 0.

Further preferred are compounds of Formula (I), wherein A is a bond.

Further preferred are compounds of Formular (I), wherein A is a group ofthe formula—B₀₋₁D-E₀₋₁_(m)-G₀₋₁-K₀₋₁-

-   -   wherein    -   the group B is an alkylene, which may be substituted by one, two        or more fluorine atoms, a —NH— group, or a heteroalkylen group,        which may be substituted by one, two or more fluorine atoms        and/or at the optionally present nitrogen atoms by an alkyl or        an acyl group;    -   the groups D independently of each other are optionally        anellated heterocycloalkylen groups with 1, 2, 3 or 4 nitrogen        atoms, which heterocycloalkylen groups may each be substituted        by one, two or more fluorine atoms and/or which each may be        substituted at one, two, three or four nitrogen atoms by an        alkyl or an acyl group;    -   the groups E independently of each other are an alkylene, which        may be substituted by one, two or more fluorine atoms, a —NH—        group, or a heteroalkylen group, which may be substituted by        one, two or more fluorine atoms and/or at the optionally present        nitrogen atoms by an alkyl or an acyl group;    -   the groups G independently of each other are optionally        anellated heterocycloalkylen groups with 1, 2, 3 or 4 nitrogen        atoms, which heterocycloalkylen groups may each be substituted        by one, two or more fluorine atoms and/or which each may be        substituted at one, two, three or four nitrogen atoms by an        alkyl or an acyl group;    -   the group K is an alkylene, which may be substituted by one, two        or more fluorine atoms, a —NH— group, or a heteroalkylen group,        which may be substituted by one, two or more fluorine atoms        and/or at the optionally present nitrogen atoms by an alkyl or        an acyl group; and    -   m=1, 2, 3 or 4.

Moreover preferred are compounds of Formula (I), wherein A is acycloalkylen or a alkylcycloalkylen group that contains 2, 3 or 4nitrogen atoms and may be substituted by one, two or more fluorine atomsand the nitrogen atoms may be substituted by an alkyl or an acyl group.

Further preferred are compounds of Formula (I), wherein A is selectedfrom the following groups which may be further substituted by one, twoor more fluorine atoms or by an alkyl group which may be substituted byone, two or more fluorine atoms, and wherein the amino groups may besubstituted by an alkyl or an acyl group:

Further preferred are compounds of Formula (I), wherein the absoluteconfiguration at C-5 of the oxazolidinone ring is (S) according to theCahn-Ingold-Prelog nomenclature system.

Moreover preferred are the following compounds:

-   7-(4-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic    acid-   9-(4-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic    acid-   [(3R)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]-1cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-1-carboxylic    acid-   7-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic    acid-   7-(4-{(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic    acid-   7-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic    acid-   9-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic    acid-   7-(4-{[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid-   7-{4-[2-(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-ethyl]-piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic    acid-   7-{4-[2-(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-ethyl]-piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic    acid-   7-{4-[2-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-2-fluoro-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolone-3-carboxylic    acid-   7-(3-{4-[5(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-azetidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid-   7-[(3R)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]-naphthyridine-3-carboxylic    acid-   7-[(3R)-3-(4-{4[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid-   1-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5S)-5-(methoxythiocarbonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]-naphthyridine-3-carboxylic    acid-   1-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5S)-5-(methylsulfanylthiocarbonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-yl)-4-oxo-1,4dihydro-[1,8]naphthyridine-3-carboxylic    acid-   1-Cyclopropyl-6-fluoro-{4-[2-fluoro-4-{(5S)-2-oxo-5-thioureidomethyl-oxazolidin-3-yl}-phenyl]-piperazin-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid

The present invention also relates to pharmacologically acceptablesalts, or solvates and hydrates, respectively, and to compositions andformulations of compounds of Formula (I). The present inventiondescribes procedures to produce pharmaceutically useful agents, whichcontain these compounds, as well as the use of these compounds for theproduction of pharmaceutically useful agents.

The pharmaceutical compositions according to the present inventioncontain at least one compound of Formula I as the active agent andoptionally carriers and/or diluents and/or adjuvants. Optionally thepharmaceutical compositions according to the present invention may alsocontain additional known antibiotics.

Examples of pharmacologically acceptable salts of sufficiently basiccompounds of Formula (I) are salts of physiologically acceptable mineralacids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; orsalts of organic acids like methanesulfonic, p-toluenesulfonic, lactic,acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylicacid. Further, a sufficiently acidic compound of Formula (I) may formalkali or earth alkaline metal salts, for example sodium, potassium,lithium, calcium or magnesium salts; ammonium salts; or organic basesalts, for example methylamine, dimethylamine, trimethylamine,triethylamine, ethylenediamine, ethanolamine, choline hydroxide,meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine orarginine salts. Compounds of Formula (I) may be solvated, especiallyhydrated. The hydratisation can occur during the process of productionor as a consequence of the hygroscopic nature of the initially waterfree compounds of Formula (I). The compounds of Formula (I) containasymmetric C-atoms and may be present either as achiral compounds,mixtures of diastereomers, mixtures of enantiomers or as optically purecompounds.

The present invention also relates to pro-drugs which are composed of acompound of Formula (I) and at least one pharmacologically acceptableprotective group which will be cleaved off under physiologicalconditions, such as an alkoxy-, aralkyloxy-, acyl-, acyloxymethyl group(e.g. pivaloyloxymethyl), an 2-alkyl-, 2-aryl- or2-aralkyl-oxycarbonyl-2-alkylidene ethyl group or an acyloxy group asdefined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy.

As mentioned above, therapeutically useful agents that contain compoundsof Formula (I), their solvates, salts or formulations are also comprisedin the scope of the present invention. In general, compounds of Formula(I) will be administered by using the known and acceptable modes knownin the art, either alone or in combination with any other therapeuticagent. Such therapeutically useful agents can be administered by one ofthe following routes: oral, e g. as tablets, dragees, coated tablets,pills, semisolids, soft or hard capsules, for example soft and hardgelatine capsules, aqueous or oily solutions, emulsions, suspensions orsyrups, parenteral including intravenous, intramuscular and subcutaneousinjection, e.g. as an injectable solution or suspension, rectal assuppositories, by inhalation or insufflation, e.g. as a powderformulation, as microcrystals or as a spray (e.g. liquid aerosol),transdermal, for example via an transdermal delivery system (TDS) suchas a plaster containg the active ingredient or intranasal. For theproduction of such tablets, pills, semisolids, coated tablets, drageesand hard, e.g. gelatine, capsules the therapeutically useful product maybe mixed with pharmaceutically inert, inorganic or organic excipients asare e.g. lactose, sucrose, glucose, gelatin, malt, silica gel, starch orderivatives thereof, talc, stearinic acid or their salts, dried skimmilk, and the like. For the production of soft capsules one may useexcipients as are e.g. vegetable, petroleum, animal or synthetic oils,wax, fat, polyols. For the production of liquid solutions, emulsions orsuspensions or syrups one may use as excipients e.g. water, alcohols,aqueous saline, aqueous dextrose, polyols, glycerin, lipids,phospholipids, cyclodextrins, vegetable, petroleum, animal or syntheticoils. Especially preferred are lipids and more preferred arephospholipids (preferred of natural origin; especially preferred with aparticle size between 300 to 350 nm) preferred in phosphate bufferedsaline (pH=7 to 8, preferred 7.4). For suppositories one may useexcipients as are e.g. vegetable, petroleum, animal or synthetic oils,wax, fat and polyols. For aerosol formulations one may use compressedgases suitable for this purpose, as are e.g. oxygen, nitrogen and carbondioxide. The pharmaceutically useful agents may also contain additivesfor conservation, stabilisation, e.g. UV stabilizers, emulsifiers,sweetener, aromatisers, salts to change the osmotic pressure, buffers,coating additives and antioxidants.

A daily dosage per patient of about 1 mg to about 4000 mg especiallyabout 50 mg to 3 g is usual with those of ordinary skill in the artappreciating that the dosage will depend also upon the age, conditionsof the mammals, and the kind of diseases being treated or prevented. Thedaily dosage can be administrated in a single dose or can be dividedover several doses. An average single dose of about 50 mg, 100 mg, 250mg, 500 mg, 1000 mg and 2000 mg can be contemplated.

The compounds of Formula (I) can for example be obtained by reacting anoxazolidinone bearing a group A as defined above that contains an aminewith a 7-chloro or 7-fluoro quinolone derivative. To facilitate thereaction the quinolone reactant may be activated prior to its use byforming a complex with a Lewis acid like BF₃-etherate or any boroncontaining complex like boron acetate. The reaction is performed in apolar solvent like acetonitrile, 1-methyl-2-pyrrolidone, water, DMSO inpresence of an organic base like triethylamine,N,N′dimethyl-p-toluidine, N-methylmorpholine, DBU, DABCO between 20 and200° C. preferably between 80 and 130° C. The reaction can be performedunder microwave activation

Alternatively, the product can be prepared from the corresponding7-chloro-quinolone by substitution with a 4-nitrophenyl derivativebearing a group containing an amine and subsequent construction of theoxazolidinone through reduction of the nitro group, reaction with benzylchloroformate, deprotonation with n-BuLi and reaction with a glycitolester.

In the following the invention is described in more detail withreference to examples. These examples are intended for illustration onlyand are not to be construed as any limitation.

EXAMPLES Example 17-(4-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A mixture of7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylateboron diacetate (described in WO8807998; 103 mg, 0.25 mmol),N-[3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidinon-5-ylmethyl]acetamide(described in J. Med Chem 1996, 39, 673-679 and U.S. Pat. No. 5,547,950;100 mg, 0.3 mmol) and N,N′dimethyl-p-toluidine (0.054 ml, 0.375 mmol)were stirred at 120° C. in 0.5 ml of 1-methyl-2-pyrrolidone for 12hours. The reaction mixture was poured into water and the resultingcrystals were collected by filtration and purified by chromatographyover silicagel. The interesting fractions were pooled affording 38 mg(26%) of beige material.

C₂₉H₂₉F₂N₅O₆ (581.5812)

mp 315-320° C. (dec)

MS: 582.4 (M+H); 580.4 (M−H).

Example 29-(4-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylicAcid

A suspension of9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[1,2,3-de]-1,4-benzoxazine-6-carboxylicacid (commercially available from Aldrich (47267-0) and described inChem. Pharm. Bull. 1987, 35, 1896-1902, 84 mg; 0.3-mmol),N-[3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidinon-5-ylmethyl]acetamide(described in J. Med Chem 1996, 39, 673-9 and U.S. Pat. No. 5,547,950;121 mg, 0.36 mmol) and DABCO (43.7 mg, 0.39 mmol) in acetonitrile/water(7 ml, 2:1) was refluxed for 12 days. The acetonitrile was removed underreduced pressure and the residue was poured into water. The crystalswere collected by filtration and further stirred in methanol (5 ml). Theresulting crystals were recrystallised from DMF/water (4:1) affording 95mg of beige material (53%).

C₂₉H₂₉F₂N₅B (597.5806)

mp 258° C. (dec)

MS: 596.8 (M−H); 598.5 (M+H)

Example 37-((3R,S)-3-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylcarbamoyl}-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

2([(5S)-5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylcarbamoyl)-piperazine-1,4-dicarboxylicAcid Di-Tert-Butyl Ester

0.210 ml of phosphoroxychloride was added at −15° C. to a solution of0.4 gN[(5S)-3-(4-amino-3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]acetamide(1.5 mmol) and 0.545 g piperazine-1,2,4-tricarboxylic acid1-4-di-tert-butyl ester (1.65 mmol) in 10 ml pyridine. The reaction wasmonitored by TLC. The reaction mixture was poured on ice, diluted withdichloromethane, the org. layer washed with water and brine, dried overMg sulfate, filtered and evaporated. The residue was purified bychromatography, using a dichloromethane/methanol 95/5 as eluent leavinga colorless foam.

Yield: 0.390 g. 45%, C27H38FN5O8 (579.63), MS: 580.5 (M+H)⁺, 578.8(M−H)⁻ Method ESI⁺, ESI⁻.

(2R,S)-2([(5S)-5-(Acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylcarbamoyl)-piperazine

A solution of 0.376 g2([(5S)-5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylcarbamoyl)-piperazine-1,4-dicarboxylicacid di-tert-butyl ester in 10 ml of dichloromethane was diluted with 10ml of 1.25 N HCl in methanol. The reaction was monitored by TLC. Thesolvents were evaporated, the residue dissolved in 10 ml water,neutralized with sodium bicarbonate, and the water layer evaporated todryness. The residue was digested in a 1/1 dichloromethane/methanolsolution, the insoluble salts filtered, and the filtrate evaporated. Theresidue was digested in ethyl acetate and the solid filtered.

Yield: 0.250 g, quant. C17H22FN5O4 (379.39), MS: 380.5 (M+H)⁺, method:ESI⁺.

7-((3R,S)-3-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylcarbamoyl}-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A mixture of 175 mg2([5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylcarbamoyl)-piperazine(0.46 mmol), 188 mg7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoborondiacetate and 154 mg of 1,4-diazabicyclo[2.2.2]octane (1.38 mmol) in 2ml of N-methyl pyrrolidone was stirred at 100° C. under inert gas. Thereaction was monitored by TLC. The mixture was poured in ether, thesolid filtered and dried. The solid was purified by chromatography,using a dichloromethane/methanol 9/1 mixture with 1% acetic acid. Thefractions with a rf of 0.1 were collected and evaporated.

Yield: 0.043 g, 18%. C30H30F2N6O7 (624.61), MS: 625.5 (M+H)⁺,623.8(M−H)⁻.

Known building blocks:

-   piperazine-1,2,4-tricarboxylic acid 1-4-di-tert-butyl ester: CAS    181955-79-3; Com. Source: Chem. Pacific Product List No 33681,-   7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoboron    diacetate: Ger. Offen. (1996), DE 4428985.-   (S)-N[3-(4-amino-3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]acetamide:    Genin, Michael et al. Journal of Medicinal Chemistry (2000), 43(5),    953-970

Example 47-[(3R)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]-1cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-1-carboxylicAcid

(3R)-3-(2-Fluoro-4-nitro-phenylamino)-pyrrolidine-1-carboxylic AcidAllyl Ester

A solution of 5.01 g of 3,4-difluoro nitrobenzene, 5.1 g(3R)-1-allyloxycarbonyl-3-amino pyrrolidine (30 mmol) and 6.27 ml oftriethylamine (31.5 mmol) in 100 ml of ethyl acetate was stirred atreflux. The reaction was monitored by HPLC. The reaction was dilutedwith ethyl acetate, washed with water and brine, the org. layer driedover Mg sulfate, filtered and evaporated. The residue crystallized froman ether/hexane mixture.

Yield: 5.76 g, 59%. MW: 309.29 C14H16FN3O4

1H-NMR (δ ppm, 400 MHz, D6-DMSO): 1.09-2.24(m,2H, N—CH2—CH2-CH);3.29-3.72(m, 4H,CH2—N—CH2); 4.21-4.28(m,1H, N—CH); 4.52,(d,2H, O—CH2);5.15-5.32, (m,2H, CH═CH2); 5.87-5.99,(m,1H, CH═CH2); 6.94,(t, 1H,Ph-CH); 7.19,(d,1H, NH); 7.9-7.99,(m,2H, Ph-CH);

(3R)-3-(2-Fluoro-4-nitro-phenylamino)-pyrrolidine-1-carboxylic AcidTert-Butyl Ester

To a solution of 5.76 g(3R)-3-(2-fluoro-4-nitro-phenylamino)-pyrrolidine-1-carboxylic acidallyl ester (18.6 mmol) in 60 ml THF were added 130 mg of PdCl₂{P(Ph)₂}(0.186 mmol), 12.12 ml acetic acid (37.2 mmol), and 49.87 ml tributyltinnhydride (37.2 mmol). The reaction was stirred at rt for 1 hr. andmonitored by TLC. A pale yellow solid precipitated. The suspension wasdiluted with 100 ml ether, the solid was filtered, washed with ether andhexane and dried. The solid was suspended in 10 ml THF, 4.87 g BOCanhydride (, 30 mmol) was added and the reaction stirred at rt. for 3 hand monitored by TLC. The reaction was diluted with ethyl acetate, theorg layer washed with water and brine, dried over Mg sulfate, filteredand the filtrate evaporated. The residue was crystallized from anether/hexane mixture.

Yield: 4.15 g, 68%. MW: 325.34 (C15H20FN3O4)

1H-NMR (400 MHz, D6-DMSO; δ ppm): 1.25,(s,9H,t-but); 1.75-2.07(m,2H,N—CH2—CH2-CH); 3.07-3.5(m, 4H,CH2—N—CH2); 4.05-4.1(m,1H, N—CH);6.77-6.83,(t, 1H, Ph-CH); 7.01,(d,1H, NH); 7.77-7.858, (m,2H, Ph-CH);

(3R)-3-[Benzyloxycarbonyl-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-amino]-pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

To a solution of 4 g of(3R)-3-(2-fluoro-4-nitro-phenyl-amino)-pyrrolidine-1-carboxylic acidtert-butyl ester (12.29 mmol) in 100 ml ethyl acetate and 50 ml methanolwere added 1 g of Pd/C 10%. The suspension was stirred under hydrogen.The reaction was monitored by TLC. The catalyst was filtered, thefiltrate evaporated to dryness, and the residue was dissolved in 100 mlof acetone. 25 ml of a saturated solution of sodium bicarbonate wasadded, than a 0° C. 3.63 ml of benzyl chloroformate (25.8 mmol). Thereaction was stirred over night at rt and monitored by TLC. The acetonewas evaporated, the water layer extracted twice with ethyl acetate, theorg layer washed with water and brine, dried over Mg sulfate, filteredand the filtrate evaporated to dryness. The residue was purified bychromatography, using a 1/1 ethyl acetate/hexane mixture as eluent.

Yield: 6.03 g, 99%. MW: 563.63, C31H34FN3O6, MS: 562.4 (M−H)⁻, MethodESI⁻.

(3R)-3-{Benzyloxycarbonyl-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-amino}-pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

To a solution of 6.02 g(3R)-3-[benzyloxycarbonyl-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-amino]-pyrrolidine-1-carboxylicacid tert-butyl ester (10.8 mmol) in 40 ml THF at −78° C. was addeddropwise 7.62 ml of a 1.6 M N-butyl-lithium solution in N-hexane (12.2mmol). The mixture was stirred at −78° C. for 10 min, than allowed toreach 0° C. 2.11 g of R(−)-glycidyl butyrate (14.6 mmol) was added. Thereaction was allowed to reach 20° C. and was monitored by TLC. Thereaction was diluted with ethyl acetate, washed with water and brine,dried over Mg sulfate, filtered and the filtrate evaporated. The residuewas crystallized from an ethyl acetate/hexane mixture.

Yield: 3.36 g, 60%. MW: 529.47, (C27H32FN3O7) MS: 530.3 (M+H)⁺, MethodESI⁻.

(3R)-3-{[4-{(5R)-5-Azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-benzyloxycarbonyl-amino}-pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

To a solution 3.36 g of(3R)-3-{benzyloxycarbonyl-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester (10.8 mmol) and 2.05 ml of triethylamine (10.8mmol) in 40 ml of dichloromethane, was added at 0° C. 0.805 ml ofmethanesulfonyl chloride (10.8 mmol). The reaction was stirred at rt.and monitored by TLC. The reaction was diluted with water and washedwith water and brine. The org. layer was dried over Mg sulfate, filteredand the filtrate evaporated The solid residue was dissolved in 10 ml ofDMF and 1.38 g sodium azide (10.8 mmol) was added and the mixturestirred under inert gas at 80° C. for 20 hrs. The DMF was evaporated,the residue dissolved in ethyl acetate, washed with water and brine,dried over Mg sulfate, filtered and evaporated.

Yield: 4.07 g, 99%. MW: 554.58, (C27H31FN6O6) MS: 555.5 (M+H)⁺, MethodESI⁺.

(3R)3-{4-[(5S)-5-(Acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

To a stirred solution of 4.2 g of(3R)-3-{[4-{(5R)-5-azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-benzyl-oxycarbonyl-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester (7.3 mmol) in 50 ml ethyl acetate were added 400mg of Pd/C 10% and the mixture was stirred under hydrogen over night.The reaction was controlled by TLC. The Pd/C was filtered, the filtrateevaporated to dryness. The residue was dissolved in 5 ml acetic acid and2 ml acetic anhydride was added. The reaction was stirred at rt for 2hrs and monitored by TLC. The solvents were evaporated, the residuedissolved in ethyl acetate, washed with water and brine, dried over Mgsulfate, filtered and the filtrate evaporated to dryness.

Yield: 3.1 g, quantitative. MW: 436.48,(C21H29FN4O5) MS: 437.5 (M+H)⁺,Method ESI⁺.

N-{(5S)-3-[3-Fluoro-4-{(3R)-pyrrolidin-3-ylamino}-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

A solution of 0.93 ml triethylsilane (7.3 mmol)(3R)3-{4-[(5S)-5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidine-1-carboxylicacid tert-butyl ester (, 7.3 mmol) in 40 ml of a CH2Cl2/TFA 1/1 mixturewas stirred at rt and monitored by TLC. The solvents were evaporated,the residue dissolved in water and neutralized with a saturated sodiumbicarbonate solution. The water was evaporated, the residue digested ina 1:1 CH₂Cl₂/MeOH solution, the solution treated with 500 mg of Fuller'searth, filtered and the filtrate evaporated.

Yield: 2.1 g, 85%. MW: 336.36, (C16H21FN4O3) MS: 337.6 (M+H)⁺, MethodESI⁺.

7-[(3R)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]-1cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-1-carboxylicAcid

A solution of 204 mg7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoborondiacetate (0.5 mmol), 252 mgN-{(5S)-3-[3-fluoro-4-{(3R)-pyrrolidin-3-ylamino}-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide(0.75 mmol) and 112 mg DABCO (MW: 112.0, 1 mmol) in 5 ml DMSO wasstirred for 50 h. The DMSO was evaporated. The residue was suspended in10 ml ethanol with 100 μl triethylamine and stirred at room temperaturefor 20 hrs. The mixture was diluted with 20 ml water. The mixture wasfiltered and the solid collected. The solid was crystallized in amethanol/ethanol/dichloromethane mixture.

Yield: 16 mg, 3.6%. MW: 582.4, (C29H29F2N5O6) MS: 582.4 (M+H)⁺, MethodESI⁺.

Example 57-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

7-Chloro-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid Ethyl Ester

A solution of 0.747 g of2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylic acid ethyl ester(2.23 mmol) and 0.250 g of 2-amino-5-fluoropyridine (2.23 mmol) in 5 mlethanol was stirred at reflux for 25 hrs. The reaction was monitored byTLC. The ethanol was evaporated and the last traces of ethanol weredistilled from an azeotrope with a mixture of 10 ml heptane and 10 mlethyl acetate. The yellow oil was dissolved in 10 ml of THF, reactedwith 120 mg of a 50% NaH suspension in oil and stirred at reflux overnight. The solvent was evaporated, the residue dissolved indichloromethane/methanol 9:1, washed with water and brine, dried over Mgsulfate, filtered and evaporated. The residue was digested in ethylacetate, and the solid filtered.

Yield: 583 mg, 72%. MW: 364.73, (C17H11ClF2N2O3) MS: 365.4 (M+H)⁺,Method ESI⁺.

7-chloro-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A suspension of 0.5 g7-chloro-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid ethyl ester (1.37 mmol) in a mixture of 1.5 ml acetic acid and 1.5ml 25% HCl was stirred at 90° C. over night. The reaction was monitoredby HPLC. The suspension was poured into 50 ml water, the colorlesscrystals filtered and dried.

Yield: 461 mg, quant. MW: 336.68, (C15H7ClF2N2O3) MS: 337.5 (M+H)⁺,Method ESI⁺.

7-chloro-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylatoboronDiacetate

To a stirred suspension of 380 mg7-chloro-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (1.12 mmol) in 4 ml dichloromethane were added at 0° C. 0.31 mltriethylamine (d=0.726, 2.25 mmol) and 0.12 ml (d=1.1050, 1.68 mmol)acetyl chloride. The reaction mixture was allowed to warm up to RT,diluted with dichloromethane and washed twice with ice cold water andbrine. The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was crystallized from a dichloromethane/hexanemixture. 332 mg of the colorless crystals were suspended in 0.63 ml ofacetic anhydride (MW: 102.9, d=1.08, 6.6 mmol), 78 mg anhydrous boricacid (MW: 61.83, 1.26 mmol) and 1 mg zinc chloride (MW: 136.28, 0.7mmol) were added. The mixture was stirred at 80° C. for two hours. Thereaction was poured on 10 g ice in 20 ml water and stirred. Thecolorless crystals were filtered, digested twice in 100 ml ethanol,filtered, washed with ether and hexane, and dried at RT under vacuum.

Yield: 226 mg, 43%. MW: 464.57, (C19H12BClF2N2O7)

1H-NMR (δ ppm; DMSO-D₆): 1.96 (s, 6H, acetate); 8.15 (d, 1H, pyridin),8.25 (m, 2H, pyridin), 8.53 (d, 1H, quinoline); 8.87 (d, 1H, quinoline);9.71 (s, 1H, allyl).

7-(4-{4-(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

212 mg of7-chloro-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylatoborondiacetate (, 0.45 mmol), 306 mgN-{[(5S)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl}-acetamide(0.9 mmol) and 2 ml DMSO were irradiated in a microwave oven for 7periods of 2.30 min at 250 W in a closed reaction vessel under inertgas. The reaction was monitored by HPLC.

The DMSO was evaporated and the crude product was digested in 10 mlwater and filtered. The residue was purified by chromatography using aCH₂Cl₂/MeOH 5% mixture.

Yield: 5 mg, 2%. MW: 636.59, (C31H27F3N6O6) MS: 637.2 (M+H)⁺, MethodESI⁺.

Known building blocks:

-   2-amino-5-fluoropyridine: 21717-96-4, aldrich 51868-9-   2-(2,4-Dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylic acid ethyl ester:    86483-52-5, WO0217916 A1

Example 67-(4-{(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

7-Chloro-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid Ethyl Ester

A solution of 2 g 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylicacid ethyl ester (5.97 mmol) and 0.6 ml of 2,4-difluoroaniline (5.97mmol) in 15 ml of ethanol was stirred at reflux for 25 hrs. The reactionwas monitored by TLC. The ethanol was evaporated and the residualethanol was distilled from an azeotrope with 20 ml heptane and 20 mlethyl acetate. The yellow oil was dissolved in 20 ml of THF, reactedwith 315 mg of a 50% NaH suspension in oil (6.56 mmol) and stirred atreflux for 20 hrs. The solution was diluted with ethyl acetate, washedwith water and brine, dried over Mg sulfate, filtered and the filtrateevaporated.

Yield: 2.0 g, 90%. MW: 381.74, (C18H11ClF3NO3) MS: 382.3 (M+H)⁺, MethodESI⁺.

7-Chloro-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A mixture of 2.0 g of7-chloro-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid ethyl ester (5.23 mmol) in 16 ml acetic acid and 16 ml HCl 37% wasstirred 25 hrs at 90° C., and evaporated.

Yield: 1.71 g, quantitative. MW: 353.68, (C16H7ClF3NO3) MS: 354.3(M+H)⁺, Method ESI⁺.

7-Chloro-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylatoboronDiacetate

To a stirred suspension of 1.71 g7-chloro-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (4.84 mmol) in 4 ml of dichloromethane were successively added at0° C. 1.35 ml triethylamine (MW: 101.19, 9.68 mmol) and 0.517 ml acetylchloride (MW: 78.50, d=1.1050, 7 26 mmol). The reaction mixture wasallowed to warm up to RT, diluted with dichloromethane and washed twicewith ice cold water and brine. The org. layer was dried with sodiumsulfate, filtered and evaporated. The residue was crystallized from adichloromethane/hexane mixture.

1.91 g of the colorless crystals were suspended in 3.21 ml of aceticanhydride (33.88 mmol), 400 mg anhydrous boric acid (6.47 mmol) and 5 mgzinc chloride (0.04 mmol) were added. The mixture was stirred at 80° C.for two hours. The reaction was poured on 10 g ice in 20 ml water andstirred. The colorless crystals were filtered, digested twice in 100 mlethanol, filtered, washed with ether and hexane, and dried.

Yield: 1.7 g, 74%. MW: 481.58, (C20H12BClF3NO7) MS: 482.4 (M+H)⁺, MethodESI⁺.

7-(4-{(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A suspension of 240 mg of7-chloro-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylatoborondiacetate (0.5 mmol) and 336 mgN-({(5S)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl}-methyl)-acetamide(1 mmol) in 2 ml DMSO were irradiated in a microwave oven for three 2.30min periods at 250 W in a close reaction vessel under inert gas. Thereaction was monitored by HPLC. The DMSO was evaporated and the residuewas digested in acetonitrile/water. The solid was filtered off and thefiltrate evaporated and purified by chromatography.

Yield: 11 mg, 4%. MW: 653.60, (C32H27F4N5O6) MS: 652.5 (M−H)⁻, MethodESI⁻.

Known building blocks

-   2,4-difluoroaniline: 367-25-9, Aldrich D10-140-0-   2-(2,4-Dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylic acid ethyl ester:    86483-52-5, WO0217916 A1 20020307

Example 77-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-cyclo-propyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

1-Cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylatoboronDiacetate

To a stirred suspension of 1.12 g of1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (4 mmol) in 20 ml of dichloromethane were successively added at 0°C. 1.2 ml triethylamine (8 mmol) and 0.454 ml acetyl chloride (MW:78.50). The reaction mixture was allowed to warm up to RT, diluted withdichloromethane and washed twice with ice cold water and brine. Theorganic layer was dried with sodium sulfate, filtered and evaporated.The crystals were suspended in 3 ml of acetic anhydride (MW: 102.9, 28mmol) and 354 mg anhydrous boric acid (MW: 61.83, 5.6 mmol) and 10 mgzinc chloride (MW: 136.28, 0.07 mmol) were added. The mixture wasstirred at 80° C. for two hours. The reaction was poured on log ice in20 ml water and stirred. The colorless crystals were filtered.

Yield: 600 mg, 46%. MW: 405.14, (C18H17BFNO8) MS: 406.5, (M+H)⁺, MethodESI⁺.

7-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A solution of 100 mg1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylatoborondiacetate (0.24 mmol), 166 mg ofN-[[3-[(5S)-3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide(0.49 mmol) and 59 μl ethyldiisopropylamine (0.336 mmol) in 1 ml DMSOwas irradiated in a microwave oven for 10 min at 150° C. The reactionwas monitored by HPLC. The DMSO was evaporated and the residue waspurified by chromatography using a CH₂Cl₂/MeOH 5% mixture.

Yield: 14 mg, 10%. MW: 593.62, (C30H32FN5O7). MS: 594.6 (M+H)⁺, MethodESI⁺.

Known building blocks

-   1-Cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic    acid: 221221-16-5, U.S. Pat. No. 6,329,391-   N-[[3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide:    154590-43-9, U.S. Pat. No. 5,547,950

Example 89-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicAcid

9-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicAcid Ethyl Ester

A solution of 100 mg8,9-difluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid ethyl ester (0.32 mmol) and 216 mg ofN-[{(5S)-3[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl}-methyl]-acetamide(0.64 mmol) were dissolved in a mixture of 1 ml pyridine and 1 ml DMSO.The reaction was monitored by TLC. The DMSO was evaporated, the residuedigested in water and the solid collected. The solid was purified bychromatography, using a 9/1 dichloromethane/methanol mixture as eluent.

Yield: 44 mg 22%. MW: 626.62, (C30H32F2N6O7) MS: 627.7 (M+H)⁺, MethodESI⁺.

9-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicAcid

44 mg of9-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid ethyl ester (0.32 mmol) were heated at 80° C. in 2 ml of a 1/1conc. HCl and acetic acid mixture. The reaction was monitored by HPLC.The HCl/AcOH mixture was evaporated, the residue dissolved in amethanol/dichloromethane 1/1 mixture, treated with triethylamine andevaporated. The deacetylated residue was dissolved in a 1/1 mixtureacetic acid and acetic anhydride, and the reaction monitored by HPLC.The solvents were evaporated and the residue was purified by preparativeHPLC.

Yield: 9.1 mg 21%. MW: 598.56, (C28H28F2N6O7) MS: 599.2 (M+H)⁺, 597.7(M−H)⁻, Method ESI⁺, ESI⁻.

Example 97-{(3RS)-3-[({4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-ethyl-amino)methyl]-piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

(1,4-Dibenzyl-piperazin-2-ylmethylen)-ethyl-amine

To a solution of 0.5 g (1,4-bis(phenylmethyl)-2-piperazin-carboxaldehydin 5 ml of dichloromethane was added 0.54 ml ethylamine and 0.5 gmolecular sieves. The reaction mixture was stirred for 30 min at rt thenfiltered. The filtrate was evaporated to dryness.

Yield: 385 mg, 71%. MW: 321.46, (C21H27N3)

1H-NMR (400 MHz, D6-DMSO; δ ppm): 1.07(t,3H, N—CH2—CH3); 2.07-2.22(m,3H, N—CH2); 2.63-2.73(m,3H, N—CH2) 2.92(m,1H, pip.H2); 3.25-3.74(AB,2H,CH2-Ph); 3.41-3.53(AB,2H, CH2-Ph); 7.22-7.35(m,10H,Ph); 7.6(d,1H,methylene).

[(2R,S)-(1,4-Dibenzyl-piperazin-2-ylmethyl)]-ethyl-amine

0.92 g of sodium borohydride were added to a stirred solution of 5.24 gof [(2R,S)-1,4-dibenzyl-piperazin-2-ylmethylen]-ethylamine in 50 ml dryTHF and 3 ml ethanol under inert gas. The reaction mixture was stirredat rt for 6 hrs. Second and third portions of 0.92 g of sodiumborohydride were added after 8 and 12 hrs respectively. The reaction wasquenched with 20 ml of HCl 0.1M. The reaction mixture was diluted withethyl acetate and the organic layer was washed with water and brine,dried over MgSO4, filtered and the filtrate evaporated to give 5.5 g ofan oil. The oil was purified by chromatography over SiO2 with a 1/1hexane/acetone mixture with 1% triethylamine.

Yield: 2.1 g, 40%. MW: 323.48, (C21H29N3)

¹H-NMR (400 MHz, D₆-DMSO; δ ppm): 0.91(t,3H, N—CH2—CH3); 2.07-2.23(m,3H, N—CH2); 2.38-2.52(m,4H, N—CH2); 2.60-2.70(m, 4H, N—CH, N—CH2);3.21-3.26 and 3.97-4.01(AB,2H, CH2-Ph); 3.36-3.47(AB,2H, CH2-Ph);7.18-7.33 (m,10H, Ph-H).

[(2R,S)-1,4-Dibenzyl-piperazin-2-ylmethyl]-ethyl-(2-fluoro-4-nitro-phenyl)-amine

A mixture of 1.057 g of 3,4-difluoro-nitrobenzene (6.34 mmol), 2.05 g[(2R,S)1,4-dibenzyl-piperazin-2-ylmethyl]-ethylamine (6.34 mmol) and 1.4ml triethylamine (9.9 mmol) in 10 ml of ethyl acetate was stirred at 60°C. The reaction was monitored by TLC. The reaction was diluted withethyl acetate, washed with water and brine, dried over Mg sulfate andfiltered. The filtrate was evaporated and the residue was purified bychromatography using an ethyl acetate/hexane 3/7 mixture as eluent. Theinteresting fractions were collected and evaporated to leave a yellowsticky oil.

Yield: 2.58 g, 88%. MW: 462.57, (C27H31FN4O2) MS: 463.3 (M+H)⁺, MethodESI⁺.

(4-[{(2R,S)-1,4-Dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl)-carbamicAcid Benzyl Ester

To a solution of 2.58 g((2R,S)-1,4-dibenzyl-piperazin-2-ylmethyl)-ethyl-(2-fluoro-4-nitro-phenyl)-aminein 100 ml methanol was sequentially added 50 ml of a saturated solutionof ammonium chloride in water and 0.5 g zinc dust. The mixture wasvigorously stirred and monitored by TLC. The solid was filtered, thefiltrate concentrated and the solid deep red material filtered from theaqueous layer. The solid was dissolved in ethyl acetate, washed twicewith water and brine, dried over Mg sulfate, filtered and evaporated.

The deep red oily residue was dissolved in 100 ml acetone. 50 ml ofsaturated sodium bicarbonate solution was added. Under vigorousstirring, 1.17 ml of benzylchloroformate were added at 0° C. Thereaction was stirred at rt over night, the acetone evaporated and thewater layer extracted twice with ethyl acetate. The org. layer waswashed with water and brine, dried over Mg SO₄, filtered and thefiltrate evaporated. The residue was purified by chromatography, using a95/5 dichloromethane/methanol mixture as eluent.

Yield: 3.1 g, quantitative. MW: 566.72, (C35H39FN4O2)

¹H-NMR (400 MHz, D₆-DMSO; δ ppm): 0.95(t,3H, N—CH2—CH3); 2.26-2.39(m,3H, N—CH2); 2.55-2.70(m,2H, N—CH2); 2.99-3.05(m, 2H, N—CH2);3.18-3.25(m, 1H, N—CH2); 3.43-3.50(m,3H, —NH2); 4.04-5.25 and4.54-5.20(AB,4H, CH2-Ph); 3.36-3.47(AB,2H, CH2-Ph); 6.96-7.07(t, 1H,Ph-H); 7.09-7.12(dd,1H,Ph-H); 7.23-7.49(m, 16H, Ph-H); 9.82(s,1H, N—H).

(5R)-3-{4-[{(2R,S)-1,4-Dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-5-hydroxymethyl-oxazolidin-2-one

To a solution of 3.1 g(4-[{(2R,S)-1,4-dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl)-carbamicacid benzyl ester (5.4 mmol) in 25 ml THF at −78° C. was added dropwise4.38 ml of a butyl-lithium solution (1.6M, 7 mmol) in N-hexane. Themixture was stirred at −78° C. for 10 min, than allowed to reach −40° C.for 10 min. 1.28 g of R(−)-glycidyl butyrate (8.92 mmol) was added. Thereaction was allowed to reach 20° C. and was monitored by TLC. Thereaction was diluted with ethyl acetate, washed with water and brine,dried over Mg sulfate, filtered and the filtrate evaporated. The residuewas purified by chromatography, using a 92.5/7.5dichloromethane/methanol mixture as eluent.

Yield: 2.35 g 69%. MW: 532.68, (C31H37FN4O3) MS: 533.1 (M+H)⁺, MethodESI⁺.

Methanesulfonic Acid(5R)-3-{4-[{(2R,S)-1,4-Dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-2-oxo-oxazolidin-5-ylmethylEster

To a solution of 1.2 g of (5R)-3-{4-[{(2R,S)-1,4-dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-5-hydroxymethyl-oxazolidin-2-one.(2.25 mmol) and 0.5 ml of triethylamine (4.5 mmol) in 10 ml ofdichloromethane was added at 0° C. 0.272 g of methansulfonyl chloride(2.4 mmol). The reaction was stirred at 25° C. and monitored by TLC. Thereaction was quenched with water, the org. layer washed with water andbrine, dried over Mg sulfate, filtered and the filtrate evaporated. Theoily residue was purified by chromatography using a 95/5dichloromethane/methanol mixture with 0.5% triethylamine. The fractionswith a rf of 0.18 were collected and evaporated.

Yield: 1.02 g, 75%, MW: 610.75, (C32H39FN4O5S) MS: 611.1 (M+H)⁺, MethodESI⁺.

(5R)-5-Azidomethyl-3-{4-[{(2R,S)-1,4-Dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-oxazolidin-2-one

A suspension of 1.16 g of methanesulfonicacid-(5R)-3-{4-[{(2R,S)-1,4-dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-2-oxo-oxazolidin-5-ylmethylester (1.89 mmol), 0.245 mg sodium azide (MW: 65.01, 3.7 mmol) and 29 mgof sodium iodide (0.0189 mmol) in 5 ml of DMF was stirred under inertgas at 80° C. The reaction was monitored by TLC. The DMF was evaporated,the residue dissolved in ethyl acetate, washed with water and brine,dried over Mg sulfate than filtered and the filtrate evaporated. Theoily residue was purified by chromatography using a 95/5dichloromethane/methanol mixture with 0.25% triethylamine as eluent. Thefractions with a rf of 0.19 were collected and dried.

Yield: 0.89 g, 84%. MW: 557.67, (C31H36FN7O2) MS: 558.3 (M+H)⁺, MethodESI⁺.

N-[(5S)-3-{4-[{(2R,S)-(1,4-Dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-2-oxo-oxazolidin-5-ylmethyl]-acetamide

A solution of 889 mg(5R)-5-azidomethyl-3-{4-({(2R,S)-1,4-dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-oxazolidin-2-one(1.59 mmol), 459 mg triphenylphosphine (1.75 mmol) and 286 mg water(15.94 mmol) in 20 ml of THF was stirred at 50° C. for 22 hrs. Thereaction was monitored by TLC. The THF was evaporated and the residuedissolved in 2 ml acetic anhydride. The reaction was monitored by TLC.The solvent was evaporated and the residue was purified bychromatography using a 95/5 dichloromethane/methanol mixture with 0.5%triethylamine as eluent leaving a sticky oil.

Yield: 0.6 g, 65%. MW: 573.71, (C33H40FN5O3) MS: 574.2 (M+H)⁺, MethodESI⁺.

N-[(5S)-3-{4-[{(2R,S)-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-2-oxo-oxazolidin-5-ylmethyl]-acetamide

A suspension of 0.59 gN-[(5S)-3-{4-[{(2R,S)-(1,4-dibenzyl-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-2-oxo-oxazolidin-5-ylmethyl]-acetamide(1.028 mmol) and 300 mg Pd/C in 20 ml of a 1/1 ethyl acetate/methanolmixture was stirred under H2 at room temperature. The reaction wasmonitored by TLC. The Pd/C was filtered and the filtrate evaporated todryness. The glassy residue was dried.

Yield: 0.3 g, 86%. MW: 393.46, (C19H28FN5O3) MS: 394.3 (M+H), MethodESI⁺.

7-{(3R,S)-3-[({4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-ethyl-amino)methyl]-piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A suspension of 115 mg of7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoborondiacetate (0.282 mmol), 100 mgN-[(5S)-3-{4-[{(2R,S)-piperazin-2-ylmethyl}-ethyl-amino]-3-fluoro-phenyl}-2-oxo-oxazolidin-5-ylmethyl]-acetamideand 35 mg DABCO in 1 ml DMSO was heated in a micro wave oven for 10periods of 2.5 min. at 240 W. The reaction was monitored by TLC. TheDMSO was evaporated, the residue dissolved in 10 ml dichloromethane andthe solid collected. The solid was digested in 3 ml water, filtered andpurified by prep HPLC. The fractions were concentrated by evaporationand the water freezed dried.

Yield: 13.5 mg, 7.6%. MW: 638.67, (C32H36F2N6O6) MS: 639.4 (M+H)⁺,Method ESI⁺.

Known building block:

-   (1,4-Bis(phenylmethyl)-2-piperazincarboxaldehyde-   Lit. Naylor Alan and all. Eur. Pat. Appl (1989), EP 343900

Example 107-(4-{[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

7-(4-{[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

A suspension of 100 mg7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylicacid 0.35 mmol), 130 mgN-[{(5S)-3[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl]-acetamide(0.39 mmol) 119 mg triethylamine (MW: 101.19, 1.17 mmol) and 85 mgtrimethylchlorsilan (0-78 mmol) in 2 μl DMSO was heated at 150° C. understirring in a microwave oven for 10 min. The reaction was monitored byTLC. The DMSO was evaporated, the residue digested in water, filteredand the solid purified by chromatography, using dichloromethane/methanolmixture as eluent. The fractions were collected and evaporated. Theresidue was crystallized from acetonitrile.

Yield: 84 mg, 42%. MW: 582.57, (C28H28F2N6O6) MS: 583.3 (M+H)⁺, 581.6(M+H)⁻ Method ESI⁺, ESI⁻.

Known building blocks

-   7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic    acid-   Lit.: U.S. Pat. No. 4,777,175; U.S. Pat. No. 5,281,612; CAS:    100361-18-0-   N-[{(5S)-3[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl]-acetamide-   Lit. U.S. Pat. No. 5,547,950 CAS: 154590-66-6

Example 117-{4-[2-(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-ethyl]-piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

4-[2-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine1-yl)ethyl]piperazine-1-carboxylicAcid Tert Butyl Ester

A solution of 336 mg ofN-({(5S)-3-[-3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl)-acetamide(1 mmol), 308 mg of4-[2-{2-(methylsulfonyl)-oxy}-ethyl]-1-piperazinecarboxylicacid-1,1-dimethylethyl ester (1 mmol), 32.2 mg of tetrabutylammoniumiodide (0.08 mmol) and 203 mg of potassium carbonate (2.5 mmol) in 2 mlDMF was stirred at 800 for 20 h. The solvent was evaporated and theresidue purified by prep HPLC.

Yield: 200 mg, 36%. C27H41FN6O5 (Mw: 548.6) MS: (M+H)⁺ 549.5, MethodESI⁺.

N-[(5S)-3-{3-Fluoro-4-[4-(2-piperazin-1-yl-ethyl)-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5ylmethyl]-acetamide

A solution of 200 mg of4-[2-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-yl)ethyl]piperazine-1-carboxylicacid tert butyl ester (0.36 mmol) in 0.2 ml dichloromethane and 2 mltrifluoracetic acid was stirred for 10 min. The solvents wereevaporated, the residue was digested in ether and the solid filtered.The solid was dissolved in water and neutralized with a saturatedsolution of sodium bicarbonate. The water was evaporated and the productdried as a mixture with the salts.

Yield: 136 mg, 100%. C22H33FN6O3 (Mw: 448.5) MS: 449.4 (M+H)⁺, MethodESI⁺.

6.7-Difluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoboronDiacetate

To a suspension of 2 g of 1-cyclopropyl-6,7difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.754 mmol) in 30ml dichloromethane was added at 0° C., 2.10 ml triethylamine (1.52 mmol)and 804 μl acetyl chloride (1.1 mmol). The solution was allowed warm upto RT. The mixture was then diluted with dichloromethane and washedtwice with water and brine. The organic layer was dried over MG sulfate,filtered and the filtrate evaporated. The solid was suspended in 5.08 mlof acetic anhydride (5.2 mmol), 628 mg anhydrous boric acid (MW: 61.83,1 mmol) and 20 mg zinc chloride (0.14 mmol) were added. The mixture wasstirred at 80C for 20 hrs. The reaction was poured on 10-g ice in 20 mlwater and stirred. The solid was filtered.

Yield: 1.4 g 47%. C17H14BF2NO7 (Mw: 393.1) MS: 394.1 (M+H)⁺, MethodESI⁺.

7-{4-[2-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxalidin-3-yl]-2-fluoro-phenyl}-piperazin-lyl)-ethyl]-piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A mixture of 163 mg ofN-[(5S)-3-{3-fluoro-4-[4-(2-piperazin-1-yl-ethyl)-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5ylmethyl]-acetamide(0.36 mmol), 142.85 mg of6.7-difluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoborondiacetate (0.36 μmmol) and 44.77 mg DABCO (0.36 mmol) was irradiated ina micro wave oven for three periods of 3 min. The reaction was followedwith HPLC. DMSO was evaporated and the residue purified by preparativeHPLC.

Yield: 40 mg, 16%. C35H41F2N7O6; (Mw: 693.7) MS: 694.3(M+H)⁺,692.6(M−H)⁻, Method ESI⁺, Method ESI⁻.

Known building blocks:

-   1-piperazinecarboxylic acid, 4-[2-(2-[methylsulfonyl)    oxy]-ethyl]-1-piperazinecarboxylic acid-1,1-dimethylethyl ester: WO    8808424-   1-cyclopropyl-6,7 difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic    acid: EP 1160241-   N-[[3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide:    154590-43-9: U.S. Pat. No. 5,547,950

Example 127-[4-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-piperidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

1-(1-Benzyl-piperidin-4-yl)-4-(2-fluoro-4-nitro-phenyl)-piperazine

To a solution of 10 g of 2,2-((2-fluoro-4-nitrophenyl)-imino]bis-ethanol(40.5 mmol) and 12.3 g triethylamine (120 mmol) in 200 mldichloromethane at 0° C. were added 11.12 g methane sulfonylchloride(97.3 mmol). The reaction mixture was stirred at rt and monitored byTLC. The mixture was diluted with 50 ml dichloromethane, washed withwater, sodium bicarbonate solution and brine at 0° C. The org. layer wasdried over Mg sulfate, filtered and the filtrate evaporated to leave ayellow solid. The solid was dissolved in 200 ml toluene and 8.48 g4-amino-1-benzylpiperidine and 16.9 ml triethylamine were added. Thesuspension was stirred at 120° C. for 72 hrs. The reaction was monitoredby TLC. The solvents were evaporated, the residue dissolved in ethylacetate, washed with water and brine, dried over MG sulfate, filteredand evaporated. The residue was purified by chromatography, using a 9/1dichloromethane/methanol mixture as eluent. The interesting fractionswere collected and evaporated. The residue was crystallized from ethylacetate/hexane mixture.

Yield: 6.05 g, 40%. MW: 398.48, (C22H27FN4O2) MS: 399.4 (M+H)⁺, MethodESI⁺.

4-[4-(4-Benzyloxycarbonylamino-2-fluoro-phenyl)-piperazin-1yl]-piperidine-1-carboxylicBenzyl Ester

To a solution of 6.05 g1-(1-benzyl-piperidin-4-yl)-4-(2-fluoro-4-nitro-phenyl)-piperazine (15.2mmol) 50 ml methanol and 5 ml acetic acid was added 2 g of Pd/C 10%. Thesuspension was stirred mechanically under hydrogen. The reaction wasmonitored by TLC. The Pd/C was filtered, the filtrate evaporated todryness. The residue was dissolved in 250 ml acetone, diluted with 125ml of a saturated solution of sodium bicarbonate, and reacted with 8 mlof benzyl chloroformate. The reaction was monitored by TLC. The acetonewas evaporated, the sticky oil dissolved in ethyl acetate, washed withwater and brine and dried over Mg sulfate. The Mg sulfate was filteredand the filtrate evaporated to dryness. The residue was crystallizedfrom an ethyl acetate/hexane mixture.

Yield: 6.40 g, 77%. MW: 546.64, (C31H35FN4O4) MS: 547.4 (M+H)⁺, MethodESI⁺.

4-{4-[2-fluoro-4{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-piperazin-1-yl}-piperidin-1-carboxylicAcid Benzyl Ester

To a solution of 6.3 g4-[4-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-piperazin-1-yl]-piperidine-1-carboxylicbenzyl ester (11.52 mmol) in 60 ml of dry THF were added at −20° C.under stirring 5.7 ml of a 2.25 M LDA solution (12.8 mmol) in THF. Thereaction was allowed to warm up to 0° C., and 2.1 ml of R(−)-glycidylbutyrate (14.9 mmol) were added. The reaction was stirred at rt. andmonitored by TLC. The reaction was quenched with ammonium chloridesolution, diluted with water, and the org. layer was washed with 10%sodium bicarbonate solution and brine. The org. layer was dried over Mgsulfate and filtered. The filtrate was evaporated to dryness, and theresidue crystallized from an ethyl acetate/hexane mixture.

Yield: 3.87 g, 65.5%. MW: 512.58, (C27H33FN4O5) MS: 513.7 (M+H)⁺, MethodESI⁺.

4-{4-[4-{(5R)-5-Azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-piperazin-1-yl}-piperidin-1-carboxylicAcid Benzyl Ester

To a solution of 3.67 g4-{4-[2-fluoro-4{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-piperazin-1-yl}-piperidin-1-carboxylicacid benzyl ester (7.16 mmol) and 1.99 ml of triethylamine (, 14.3 mmol)in 50 ml dichloromethane was added at 0° C. 0.66 ml of methansulfonylchloride (, 8.59 mmol). The reaction was stirred at room temperature andmonitored by TLC. The reaction was diluted with water and washed withwater and brine. The org. layer was dried over Mg sulfate, filtered andevaporated. The oily residue was dissolved in 15 ml DMF. 100 mg oftetrabutyl ammonium iodide and 0.930 g sodium azide (14.32 mmol) wereadded and the mixture stirred under nitrogen at 80° C. The reaction wasmonitored by TLC. The DMF was evaporated, the residue dissolved in ethylacetate and washed with water and brine. The org. layer was dried overMg sulfate, filtered and evaporated. The residue was crystallized froman ethyl acetate/ether mixture.

Yield: 2.65 g, 69%. MW: 537.59, (C27H32FN7O4) MS: 538.8 (M+H)⁺, MethodESI⁺.

4-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-piperidin-1-carboxylicAcid Benzyl Ester

A solution of 2.65 g of4-{4-[4-{(5R)-5-azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-piperazin-1-yl}-piperidin-1-carboxylicacid benzyl ester (4.93 mmol), 1.55 g triphenylphosphine (5.91 mmol) and0.88 g water (49.3 mmol) in 40 ml THF was stirred at reflux for 22 hrs.The reaction was controlled by TLC. The THF was evaporated and theresidue dissolved in 10 ml acetic acid and 2 ml of acetic anhydride. thereaction was monitored by TLC. The solvents were evaporated and theresidue crystallized from ethyl acetate.

Yield: 2.57 g, 94%. MW: 553.63, (C29H36FN5O5) MS: 554.5 (M+H)⁺, MethodESI⁺.

N-{(5S)-3-[3-Fluoro-4-(4-piperidin-4-yl-piperazin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

A suspension of 500 mg of 10% Pd/C and 2.5 g4-(4-{4-[((5R)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-piperidin-1-carboxylicacid benzyl ester (, 5.51 mmol) in 50 ml methanol was stirred underhydrogen. The reaction was monitored by TLC. The Pd/C was filtered off,the filtrate evaporated to dryness and the residue digested in an ethylacetate/hexane mixture. The glassy solid was filtered, washed withhexane and dried.

Yield: 1.805 g, 78%. MW: 419.50, (C21H30FN5O3) MS: 420.5 (M+H)⁺, MethodESI⁺.

7-[4-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-piperidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A suspension of 130 mg6,7-difluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoborondiacetate (0.33 mmol), 147 mgN-{3-[3-fluoro-4-(4-piperidin-4-yl-piperazin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide(0.35 mmol) and 56 mg DABCO (0.5 mmol) in 10 ml acetonitrile were heatedunder stirring in a micro wave oven at 150° C. for 10 min. The solventswere evaporated, the residue digested over night in ethanol and thesolid filtered off. The solid was digested in a 4/1 mixture ofmethanol/1N HCl and the solid filtered.

Yield: 65 mg, 29%. MW: 664.72, (C34H38F2N6O6) MS: 665.5 (M+H)⁺, 663.4(M−H)⁻ Method ESI⁺, ESI⁻.

Example 13 7-[(3R,4R) and(3S,4S)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-4-aminomethyl-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-3-carboxylicAcid

(4-Bromo-3-fluoro-phenyl)-carbamic Acid Benzyl Ester

To a solution of 10 g of 4-bromo-3-fluoroaniline (52 mmol) in 300 mlacetone were added successively 150 ml of a saturated sodium bicarbonatesolution and at 0° C. 9 ml of benzyl chloroformate (63 mmol). Thereaction was monitored by TLC. The acetone was evaporated, the residueextracted twice with ethyl acetate, washed with water and brine, driedand evaporated. The residue was crystallized from an ethylacetate/hexane mixture.

Yield: 15.7 g, 92%. MW: 324.15, (C14H11BrFNO2) MS: 322.4 (M−H)⁻ MethodESI⁻.

3-(4-Benzyloxycarbonylamino-2-fluoro-phenyl)-acrylic Acid Ethyl Ester

A suspension of 9.72 g (4-bromo-3-fluoro-phenyl)-carbamic acid benzylester (30 mmol), 6 g ethyl acrylate (60 mmol), 10.2 ml DIPEA (60 mmol),112 mg palladium acetate (, 3 mmol), and 1.57 g triphenylphosphine (6mmol) in 10 ml DMF were stirred at 130° C. for 48 h. The reaction wasmonitored by TLC. The DMF was evaporated, the residue dissolved indichloromethane, washed with water and brine, dried over Mg sulfate,filtered and the filtrate evaporated. The residue was purified bychromatography, using a 7/3 N-hexane/ethyl acetate mixture as eluent.

Yield: 4.50 g, 43%. MW: 343.35, (C19H18FNO4) MS: 342.1 (M−H)⁻ MethodESI⁻.

(3S,4R) and(3R,4S)-1-Benzyl-4-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-pyrrolidine-3-carboxylicAcid Ethyl Ester

To a solution of 4.5 g of3-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-acrylic acid ethyl ester (,13.1 mmol) and 7.68 gN-[(pentyloxy)methyl]-N-[(trimethylsilyl)-methyl]-benzenemethanamine(26.2 mmol) in 50 ml dichloromethane was added 10 μL. trifluoroaceticacid. The reaction was monitored by TLC. The reaction was complete after10 min. The mixture was diluted with dichloromethane, washed with sat.sodium bicarbonate solution and brine, dried over Mg sulfate, filteredand the filtrate evaporated. The residue was purified by filtration overa short silica column, using a 7/3 hexane/ethyl acetate mixture aseluent.

Yield: 4.93 g, 79%. MW: 476.55, (C28H29FN2O4) MS: 477.4 (M+H)⁺ MethodESI⁺.

[4-{(3R,4S) and(3S,4R)-1-Benzyl-4-hydroxymethyl-pyrrolidin-3-yl}-3-fluoro-phenyl]-carbamicAcid Benzyl Ester

A solution of 4.05 g (3R,4S) and(3S,4R)-1-benzyl-4-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-pyrrolidine-3-carboxylicacid ethyl ester (, 10.3 mmol) in 10 ml ether was added to a suspensionof 480 mg LAH (15.5 mmol) in 100 ml diethylether at RT. The reaction wasmonitored by TLC. The excess LAH was hydrolyzed by a saturatedsodium/potassium tartrate salt solution. The reaction was diluted withethyl acetate, washed with water and brine, dried over Mg sulfate,filtered and the filtrate evaporated to dryness. The residue wascrystallized from an ethyl acetate/hexane mixture.

Yield: 4.93 g, 79%. MW: 434.51, (C26H27FN2O3) MS: 435.6 (M+H)⁺ MethodESI⁺.

[4-{(3R,4S) and(3S,4R)-4-Azidomethyl-1-benzyl-pyrolidin-3-yl}-3-fluoro-phenyl]-carbamicAcid Benzyl Ester

This compound was synthesized in analogy to the procedure described inExample 12 with 4.73 g [4-{(3R,4S) and(3S,4R)-1-benzyl-4-hydroxymethyl-pyrrolidin-3-yl}-3-fluoro-phenyl]-carbamicacid benzyl ester (10.9 mmol).

Yield: 5.0 g, quantitative. MW: 459.52, (C26H26FN5O2) MS: 460.6 (M+H)⁺Method ESI⁺.

{4-[(3R,4S) and(3S,4R)-1-Benzyl-4(tert-butoxycarbonyl-aminomethyl)-pyrrolidin-3-yl]-3-fluoro-phenyl}-carbamicAcid Benzyl Ester

A solution of [4-{(3R,4S) and(3S,4R)-4-azidomethyl-1-benzyl-pyrolidin-3-yl}-3-fluoro-phenyl]-carbamicacid benzyl ester (10.3 mmol), 3.39 g triphenylphosphine (12.96 mmol)and 1.8 g H2O (MW: 18.0 100 mmol) in 80 ml THF was stirred at reflux for22 hrs. The reaction was controlled by TLC. 2.25 ml triethylamine (16.2mmol) and 2.82 g BOC₂O (12.9 mmol) were added and the mixture stirred atrt. The reaction was monitored by TLC. The solvent was evaporated andthe residue was purified by chromatography, using an ethylacetate/hexane 7/3 mixture as eluent.

Yield: 5.0 g, quantitative. MW: 533.64, (C31H36FN3O4) MS: 534.4 (M+H)⁺Method ESI⁺.

{(3R,4S) and(3S,4R)-1-Benzyl-4-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-pyrrolidin-3-ylmethyl}-carbamicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 12 with 4.45 g {4-[(3R,4S) and (3S,4R)-1-benzyl-4(tert-butoxycarbonylamino-methyl)-pyrrolidin-3-yl]-3-fluoro-phenyl}-carbamicacid benzyl ester (8.33 mmol).

Yield: 2.65 g, 63.6%. MW: 499.58, (C27H34FN3O5) MS: 500.4, (M+H)⁺ MethodESI⁺.

{(3R,4S) and(3S,4R)-1-Benzyl-4-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-pyrrolidin-3-ylmethyl}-carbamicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 12 with 2.60 g {(3R,4S) and(3S,4R)-1-benzyl-4-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-pyrrolidin-3-ylmethyl}-carbamicacid tert-butyl ester (5.20 mmol).

Yield: 2.70 g, quantitative. MW: 524.6, (C27H33FN6O4) MS: 525.6, (M+H)⁺Method ESI⁺.

[(3R-4S) and(3S-4R)-4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-1-benzyl-pyrrolidin-3-ylmethyl]-carbamicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 9 with 2.7 g {(3R,4S) and(3S,4R)-1-benzyl-4-(2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-pyrrolidin-3-ylmethyl}-carbamicacid tert-butyl ester (5.20 mmol).

Yield: 2.54 g, 90%. MW: 540.64, (C29H37FN4O5) MS: 541.3, (M+H)⁺ MethodESI⁺.

[(3R,4S) and(3S,4R)-4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyrrolidin-3-ylmethyl]-carbamicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 12 with 2.5 g [(3R,4S) and(3S,4R)-4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-1-benzyl-pyrrolidin-3-ylmethyl]-carbamicacid tert-butyl ester (4.6 mmol).

Yield: 1.69 g, 81%. MW: 450.51, (C22H31FN4O5) MS: 451.5, (M+H)⁺ MethodESI⁺.

7-[(3R,4R) and(3S,4S)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-4-aminomethyl-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-3-carboxylicAcid

A suspension of 130 mg6,7-difluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoborondiacetate (MW: 393.11.0.33 mmol), 163 mg [(3R-4S) and(3S-4R)-4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyrrolidin-3-ylmethyl]-carbamicacid tert-butyl ester (0.36 mmol) and 56 mg DABCO (0.5 mmol) in 10 mlacetonitrile were heated under stirring with in microwave oven at 150°C. for 10 min. The reaction was monitored by TLC. The acetonitrile wasevaporated, the residue dissolved in 3 ml methanol and treated with 3 ml1.25 M HCl in methanol. The reaction was stirred for 20 h and purifiedby preparative HPLC.

Yield: 75 mg, 36%. MW: 595.61, (C30H31F2N5O6)

MS: 596.5, (M+H)⁺ Method ESI⁺.

Example 147-{4-[2-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolone-3-carboxylicAcid

4-[2-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-piperazine-1-carboxylicAcid Tert-Butyl Ester

To a stirred suspension of 672 mg ofN-[(5S)-3-(3-fluoro-4-piperazine-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide(2 mmol) and 0.42 ml of triethylamine (3 mmol) in 30 ml dichloromethanewas added at rt. a solution of 484 mg bromoacetylbromide (2.4 mmol) in 2ml of dichloromethane. The reaction was monitored by TLC. The reactionsolution was washed with water and brine, the dichloromethane layerdried over Mg sulfate, filtered and the filtrate evaporated to dryness.The residue was digested in 20 ml ether, the solid filtered and dried.The colorless solid was dissolved in 10 ml DMF, 372 mg N-Boc piperazine2 mmol) and 276 mg of potassium carbonate (2 mmol) were added. Thereaction was stirred over night at 60° C. and monitored by TLC. The DMFwas evaporated to dryness, the residue purified by chromatography, usinga 19/1 dichloromethane/methanol mixture as eluent.

Yield: 0.494 g, 44%. MW: 562.64, (C27H39FN6O6)

MS: 563.5 (M+H)⁺, Method ESI⁺.

N-[(5S)-3-{3-Fluoro-4[4-(2-piperazin-1-yl-acetyl)-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl]-acetamide.

A solution of 0.490 g of4-[2-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (0.87 mmol) in 2 ml dichloromethane was treatedwith 2 ml of TFA. The reaction was monitored by TLC. The solvent wasevaporated and the residue dissolved in water. The water layer wasneutralized with ammonium hydroxide and freeze-dried.

Yield: 0.494 g, 44%. MW: 462.52, (C22H31FN6O4)

MS: 463.6 (M+H)⁺, Method ESI⁺.

7-{4-[2-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolone-3-carboxylicAcid

A suspension of 169 mg6,7-difluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoborondiacetate (0.33 mmol), 198 mgN-[(5S)-3-{3-fluoro-4[4-(2-piperazin-1-yl-acetyl)-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl]-acetamide(0.43 mmol), and 120 mg DABCO (1.07 mmol), in 10 ml acetonitrile wasstirred at 150° C. in a micro wave oven for 10 min. The reaction wasmonitored by TLC. The acetonitrile was evaporated, the residue dissolvedin 3 ml methanol and treated with 3 ml 1.25 M HCl in methanol. Thereaction was stirred over night, and the solid filtered off. The solidwas purified by prep HPLC.

Yield: 29 mg, 9.6%. MW: 707.74, (C35H39F2N7O7)

MS: 708.7, (M+H)⁺, 706.6, (M−H)⁻, Method ESI⁺, ESI⁻.

Example 157-(3-{4-[5(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-azetidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

(1-Benzhydryl-azetidin-3-yl)-(2-fluoro-4-nitro-phenyl)-amine

A solution of 7.96 g of 1-benzhydrylazetidin-3-ylamine (33.41 mmol),3.69 ml 3,4-difluoronitrobenzene (33.41 mmol) and 4.65 ml triethylamine(33.41 mmol)) in 50 ml ethyl acetate was stirred for 2 weeks at 60° C.The reaction was diluted with water and the product extracted with ethylacetate. The organic layer was washed with water and brine, dried overMgSO4, filtered and evaporated.

Yield: 13.2 g, quantitative. MW: 393.46, (C23H24FN3O2)

1H-NMR (δ ppm DMSO-d₆): 2.78 (m, 2H, CH₂); 3.54 (m, 2H, CH₂); 4.02 (m,1H, CH); 4.46 (s, 1H, CH); 6.69 (t, 1H, aro); 7.1-7.5 (m,8H, biphenyl);7.90 (m, 2H, aro)

3-[(Benzyloxycarbonyl-(4-benzyloxycarboylamino-2-fluoro-phenyl)-amino]-azetidine-1-carboxylicAcid Benzyl Ester

A suspension of 1 g of(1-benzhydryl-azetidin-3-yl)-(2-fluoro-4-nitro-phenyl)-amine (2.54 mmol)and 200 mg Pd/C 10% in 10 ml of a methanol with 5% acetic acid mixturewas stirred under H₂ for 20 hrs. The Pd/C was filtered off and thefiltrate evaporated. The oily residue was digested in hexane, anddecanted in order to eliminate the hexane soluble biphenylmethane. MS182 (M+H)⁺, Method ESI⁺. The remaining sticky oil was dissolved in 10 mlacetone. 10.0 ml of a saturated solution of sodium bicarbonate and 1.25ml benzyl chloroformate (7.62 mmol) were added at 0° C. The mixture wasstirred for 4 h at RT. The acetone was evaporated, and the residuediluted with ethyl acetate. The organic layer was washed with water andbrine, dried over Mg sulfate, filtered and the filtrate evaporated. Theresidue was purified by chromatography using an ethyl acetate/hexane 4/5mixture as eluent.

Yield: 916 mg, 63%. MW: 583.62, (C33H30FN3O6)

MS: 584.5 (M+H)⁺, Method ESI⁺.

3-{Benzyloxycarbonyl-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-amino}-azetidine-1-carboxylicAcid Benzyl Ester

To a solution of 0.916 g of3-(benzyloxycarbonyl-(4-benzyloxycarboylamino-2-fluoro-phenyl)-amino]-azetidine-1-carboxylicacid benzyl ester (1.56 mmol) in 5 ml THF were added at −15° C. 0.767 mlof a 2.25M LDA (1.7 mmol) solution in THF. The mixture was allowed towarm up to 0° C. and stirred for 5 min. Then, 0.26 ml of (R)-glycidylbutyrate (1.87 mmol) was added and the yellow solution was stirred for 2h at RT. The reaction was quenched with a saturated solution of ammoniumchloride. The mixture was diluted with ethyl acetate, the org. layerwashed with water and brine and dried over Mg sulfate. The residue waspurified by chromatography using a 95/5 dichloromethane/methanol mixtureas eluent.

Yield: 377 mg, 43%. MW: 549.56, (C29H28FN3O7) MS: 550.7 (M+H)⁺, MethodESI⁺.

3-{[4-{(5R)-5-Azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-benzyloxycarbonyl-amino)-azetidine-1-carboxylicAcid Benzyl Ester

To a solution of 1.08 g3-{benzyloxycarbonyl-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-amino}-azetidine-1-carboxylicacid benzyl ester (2 mmol) in 20 ml dichloromethane was added at 0° C.0.56 ml triethylamine (4 mmol) and 0.17 ml methanesulfonyl chloride (2.2mmol). The reaction was stirred at RT for 1 hr and quenched with water.The organic layer was washed with brine, dried with Mg sulfate, filteredand the filtrate evaporated. Yield: 391 mg, 90%. Ms 584.0 (M+H)⁺, MethodESI⁺.

A suspension of the intermediate, 260 mg sodium azide (65.01, 4 mmol)and 37 mg tetrabutylammonium iodide (0.1 mmol) in 15 ml DMF was stirredat 80° C. for 16 h. The DMF was evaporated. The residue was diluted withwater and ethyl acetate. The org. layer was washed with brine, driedover Mg sulfate, filtered and the filtrate evaporated.

Yield: 1.15 g, 93%. MW: 574.57, (C29H27FN6O6) MS: 575.4 (M+H)⁺, MethodESI⁺.

3-({4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-benzyloxycarbonyl-amino)-azetidine-1-carboxylicAcid Benzyl Ester

A solution of 1.15 g3-{[4-{(5R)-5-azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-benzyloxycarbonyl-amino)-azetidine-1-carboxylicacid benzyl ester (2 mmol), 0.36 ml water (20 mmol) and 0.277 gtriphenylphosphine (2.2 mmol) was stirred for 16 h at 50° C. The solventwas evaporated. The residue was dissolved in 5 ml acetic acid and 2 mlacetic anhydride. The solution was stirred for 30 min and evaporated.The residue was purified by chromatography using a 9/1 ethylacetate/methanol mixture as eluent.

Yield: 1.1 g, 93%. MW: 590.61, (C31H31FN4O7)

MS: 547.4 (M+H)⁺, 546.5(M−H)⁻, Method ESI⁺, Method ESI⁻.

N-{(5S)-3-[4-(Azetidin-3-ylamino)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

A suspension of 1.11 g of3-({4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-benzyloxycarbonyl-amino)-azetidine-1-carboxylicacid benzyl ester (1.88 mmol) and 200 mg Pd/c 10% in methanol wasstirred under hydrogen for 5 h. The Pd/C was filtered and the filtrateevaporated to dryness.

Yield: 340 mg, 56%. MW: 322.34, (C15H19FN4O3); MS: 323.5 (M+H)⁺, MethodESI⁺.

7-(3-{4-[5(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-azetidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

A solution of 85 mg of7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid 0.3 mmol), 97 mgN-{(5S)-3-[4-(azetidin-3-ylamino)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide(0.3 mmol), 40 mg triethylamine (0.4 mmol) and 0.065 mltrimethylchlorosilane (0.6 mmol) in 2 ml DMSO was heated at 150° C.under stirring in a microwave oven for 10 min. The reaction wasmonitored by HPLC. The DMSO was evaporated, the residue digested inwater, filtered and the solid purified by chromatography, using a 95/5dichloromethane/methanol mixture as eluent.

Yield: 52 mg, 30%. MW: 568.54, (C27H26F2N6O6) MS: 569 (M+H)⁺, MethodESI⁺.

Known building block:

-   1-benzhydrylazetidin-3-ylamine, 40432-52-8, Beta Pharma Catalog

Example 167-[(3R)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]-naphthyridine-3-carboxylicAcid

7-[(3R)-3-{4-[(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

A suspension of 119 mgN-{(5S)-3-[3-fluoro-4-(pyrrolidin-3-ylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide(0.35 mmol), 100 mg7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, 148 μl triethylamine (,1.05 mmol) and 89 μl trimethylchlorosilane(0.70 mmol) in 2 ml DMSO was stirred in a microwave oven at 150° C. for10 min. The DMSO was evaporated, the residue digested in water and thesolid filtrated. The solid was purified by chromatography using a 95/5dichloromethane/methanol mixture.

Yield: 10 mg, 5%. MW: 582.56, (C28H28F2N6O6) MS: 583.2 (M+H)⁺, MethodESI⁺.

Known buiding blocks:

-   7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-Naphthyridine-3-carboxylic    acid: CAS 100361-18-0, Louston International.

Example 17 7-[(3R,4S) and(3S,4R)-3-(−4{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}piperazine-1-carbonyl)-4-aminomethyl-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolineCarboxylic Acid

(3R,4R) and(3S,4S)-1-Benzyl-4-(tert-butoxycarbonylamino-methyl)-pyrrolidine-3-carboxylicAcid Ethyl Ester

To a solution of 2 g of 4-tert-butoxycarbonylamino-but-2-enoic acidethyl ester (8.72 mmol) and 5.12 gN-[(pentyloxy)methyl]-N-[(trimethylsilyl)methyl]-benzene-methanamine(17.4 mmol) in 50 ml dichloromethane was added 10 micro-l.trifluoroacetic acid. The reaction was monitored by TLC. The reactionwas complete after 10 min. The mixture was diluted with dichloromethane,washed with sat. sodium bicarbonate solution and brine, dried over Mgsulfate, filtered and the filtrate evaporated. The residue was purifiedby filtration over a short silica column, using a 7/3 hexane/ethylacetate mixture as eluent.

Yield: 2.96 g, 93%. MW: 362.47, (C20H30N2O4) MS: 363.6 (M+H)⁺, MethodESI⁺.

(3R,4R) and(3S,4S)-1-Benzyl-4-(tert-butoxycarbonylamino-methyl)-pyrrolidine-3-carboxylicAcid

To a solution of 2.9 (3R,4R) and(3S,4S)-1-benzyl-4-(tert-butoxycarbonylamino-methyl)-pyrrolidine-3-carboxylicacid ethyl ester (8.0 mmol) in 50 ml THF were added 671 mg lithiumhydroxide mono hydrate (, 16 mmol) and 0.5 ml water. The solution wasstirred at 40° C. and the reaction monitored by TLC. After 72 h thesolvent was evaporated, the residue dissolved in dichloromethane, washedwith water and brine, dried over Mg sulfate, filtered and evaporated.The residue was crystallized from a dichloromethane/hexane mixture.

Yield: 1.9 g, 71%. MW: 334.41, (C18H26N2O4) MS: 335.3 (M+H)⁺, 333.3(M−H)⁻, Method ESI⁺, ESI⁻.

[(3R,4R) and(3S,4S)-4-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-carbonyl)-1-benzyl-pyrrolidin-3-ylmethyl]-carbamicAcid Tert-Butyl Ester

To solution of 0.668 g of1-benzyl-4-(tert-butoxycarbonyl-amino-methyl)-pyrrolidine-3-carboxylicacid (2 mmol), 0.6 ml triethylamine (4 mmol), and 0.662 gN-[{(5S)-3[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl]-acetamide(2 mmol) in 50 ml dry DMF was added 0.796 g ofO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate,(252.1 mmol). The reaction was stirred at rt. for 20 hrs. The DMF wasevaporated, the residue dissolved in ethyl acetate, washed with waterand brine, dried over Mg sulfate, filtered and the filtrate evaporated.The residue was purified by chromatography, using a 9/1dichloromethane/methanol mixture as eluent.

Yield: 1.14 g, 87%. MW: 652.77, (C34H45FN6O6) MS: 653.7 (M+H)⁺, MethodESI⁺.

[[(3R,4R) and(3S,4S)-4-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-carbonyl)-pyrrolidin-3-ylmethyl]-carbamicAcid Tert-Butyl Ester

A suspension of 1.1 g [(3R,4R) and (3S,4S)-4-(4-{4-((5S)-5(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-carbonyl)-1-benzyl-pyrrolidin-3-yl-methyl]-carbamicacid tert-butyl ester (1.68 mmol) and 0.2 g Pd/C 10% in 10 ml methanoland 2 ml acetic acid was stirred under hydrogen. The reaction wasmonitored by TLC. The solvent was evaporated to leave an amorphoussolid.

Yield: 1.14 g, 87%. MW: 562.64, (C27H39FN6O6) MS: 563.3, (M+H)⁺, MethodESI⁺.

7-[(3R,4S) and(3S,4R)-3-(−4{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}piperazine-1-carbonyl)-4-aminomethyl-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolineCarboxylic Acid

A solution of 141 mg [[(3R,4R) and(3S,4S)-4-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-carbonyl)-pyrrolidin-3-ylmethyl]-carbamicacid tert-butyl ester (0.25 mmol), 102 mg7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylatoborondiacetate (0.25 mmol) and 61 mg DABCO (0.5 mmol) in 2 ml DMSO wasstirred at 150° C. for 12 min in a microwave oven. The reaction wasmonitored by TLC. The DMSO was evaporated, the residue dissolved inacetonitrile, diluted with water and concentrated. The solid wasfiltered and purified by prep HPLC.

Yield: 20 mg, 11.3%. MW: 707.74, (C35H39F2N7O7) MS: 708.7, (M+H)⁺,Method ESI⁺.

Example 18 7-[(3R,4S) and(3S,4R)-3-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-carbonyl)-4-aminomethyl-pyrrolidin-1-yl)1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

7-[(3R,4S) and(3S,4R)-3-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-carbonyl)-4-aminomethyl-pyrrolidin-1-yl)1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

A solution of 99 mg7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylicacid (0.35 mmol), 197 mg [(3R,4R) and(3S,4S)-4-(4-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-carbonyl)-pyrrolidin-3-ylmethyl]-carbamicacid tert-butyl ester (0.35 mmol), 146 microL triethylamine (1.05 mmol)and 76 mg trimethylchlorsilane (0.70 mmol) were dissolved in 2 ml DMSO.The solution was heated at 150° C. under stirring in a microwave ovenfor 10 min. The reaction was monitored by TLC. The DMSO was evaporated,the residue digested in water, filtered and the solid purified bychromatography, using dichloromethane/methanol mixture as eluent. Theintermediate was crystallized from acetonitrile. The crystals weredissolved in a 1.25 M HCl and stirred at rt. The reaction was monitoredby TLC. The methanol was evaporated and the residue purified bypreparative HPLC.

Yield: 130 mg, 52 A. MW: 708.72, (C34H38F2N8O7) MS: 709.6,(M+H)⁺, MethodESI⁺.

Example 197-(4-{5-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-pyridin-2-yl}-1-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

4-(Benzyloxycarbonylamino-pyridin-2-yl)-piperazine-1-carboxylic AcidTert-Butyl Ester

To a solution of 4 g 4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylicacid tert-butyl ester (12.9 mmol) in 50 ml ethyl acetate and 50 mlmethanol was added 0.5 g Pd/C 10%. The suspension was stirred under ahydrogen atmosphere. The reaction was monitored by TLC. The Pd/C wasfiltered, the filtrate evaporated to dryness, the residue dissolved in150 ml acetone, diluted with 75 ml of a saturated solution of sodiumbicarbonate, and reacted with 2.65 g of benzyl chloroformate (15.56mmol).The reaction was monitored by TLC. The acetone was evaporated, theresidue dissolved in ethyl acetate, the org. layer washed with water andbrine, dried over Mg sulfate, filtered and the filtrate evaporated todryness. The residue was crystallized from an ethyl acetate/hexanemixture.

Yield: 4.79 g, 89%. MW: 412.49, (C22H28N4O4) MS: 413.4, (M+H)⁺, MethodESI⁺.

4-[(5R)-5-(Hydroxymethyl-2-oxo-oxazolidin-3-yl)-pyridin-2-yl]-piperazine-1-carboxylicAcid Tert-Butyl Ester

To a stirred solution of 4.69 g4-(benzyloxycarbonylamino-pyridin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester (11.37 mmol) in 50 ml of THF at −70 C was added 7.46 mlof a 1.6M n-BuLi solution in N-hexane (11.93 mmol). The mixture wasstirred at 0 C for 15 min, and 2.06 ml of R(−)-glycidyl butyrate (14.7mmol) was added. The reaction was monitored by TLC. The reaction wasthen quenched with a saturated solution of ammonium chloride, dilutedwith ethyl acetate and washed with water and brine. The org. layer wasdried over Mg sulfate, filtered and the filtrate evaporated to dryness.The residue was purified by chromatography, using an ethylacetate/dichloromethane 9/1 mixture as eluent.

Yield: 2.58 g, 60%. MW: 378.43, (C18H26N4O5) MS: 379.6 (M+H)⁺, MethodESI⁺.

4-[(5R)-5-(Azidomethyl-2-oxo-oxazolidin-3-yl)-pyridin-2-yl]piperazine-1-carboxylicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 12 using 2.5 g4-[(5R)-5-(hydroxymethyl-2-oxo-oxazolidin-3-yl)-pyridin-2-yl]-piperazine-1-carboxylicacid tert-butyl ester (6.62 mmol).

Yield: 2.3 g, 86%. MW: 403.44, (C18H25N7O4) MS: 404.4, (M+H)⁺, MethodESI⁺.

4-{5-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl-pyridin-2-yl}-piperazine-1-carboxylicAcid Tert-Butyl Ester

A suspension of 2.25 g of4-[(5R)-5-(azidomethyl-2-oxo-oxazolidin-3-yl)-pyridin-2-yl]piperazine-1-carboxylicacid tert-butyl ester (6.62 mmol), and Pd/C 10% in methanol was stirredunder hydrogen. The reaction was monitored by TLC. The solvent wasevaporated and the residue dissolved in 10 ml acetic acid. 2 ml ofacetic anhydride were added to the solution and the reaction monitoredby TLC. The solvent was evaporated and the residue purified bychromatography, using a dichloromethane/methanol 9/1 mixture as eluent.

Yield: 0.572 g, 24%. MW: 419.48, (C20H29N5O5) MS: 420.4, (M+H)⁺, MethodESI⁺.

N-[(5S)-2-oxo-3-(6-piperazin-1-yl-pyridin-3-yl)-oxazolidin-5-ylmethyl]-acetamide

0.54 g of4-{5-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-pyridin-2-yl}-piperazine-1-carboxylicacid tert-butyl ester (1.28 mmol) was dissolved in a 1.25 M HCl solutionin methanol. The solution was stirred and the reaction monitored by TLC.The methanol was evaporated, the residue dissolved in water, neutralizedwith sodium bicarbonate and the water evaporated to dryness. The residuewas digested in a 9/1 dichloromethane/methanol. The insoluble salt wasfiltered off, the filtrate evaporated to dryness to leave a pale brownsolid.

Yield: 0.381 g, 93%. MW: 3198.36, (C15H21N5O3) MS: 320.1, (M+H)⁺, MethodESI⁺.

7-(4-{5-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-pyridin-2-yl}-1-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

This compound was synthesized in analogy to the procedure described inExample 10 using 0.135 gN-[2-oxo-3-(6-piperazin-1-yl-pyridin-3-yl)-oxazolidin-5-ylmethyl]-acetamide(0.42 mmol) and 120 mg7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylicacid (0.42 mmol).

Yield: 0.113 g, 47%. MW: 565.57, (C27H28FN7O6) MS: 566.8, (M+H)⁺; 564.8,(M−H)⁻, Method ESI⁺, ESI⁻.

Example 207-(4-{5-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-pyridin-2-yl}-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A solution of 127 mg(S)-N-[2-oxo-3-(6-piperazin-1-yl-pyridin-3-yl)-oxazolidin-5-ylmethyl]-acetamide(0.4 mmol), 163 mg7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylatoborondiacetate (0.4 mmol) and 90 mg DABCO in 2 ml DMSO was stirred at 150° C.for 12 min. in a microwave oven. The reaction was monitored by TLC. TheDMSO was evaporated, the residue digested in water. The solid wasfiltered and purified by chromatoghraphy, using dichloromethane/methanolas eluent.

Yield: 0.027 g, 11.9%. MW: 564.58, (C28H29FN6O6) MS: 565.8 (M+H)⁺, 563.6(M−H)⁻, Method ESI⁺, ESI⁻.

Example 217-[(3R)-3-(4-{4((5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

(3R)-3-[4-(2-Fluoro-4-nitro-phenyl)-piperazin-1-yl]-pyrrolidine-1-carboxylicAcid Allyl Ester

This compound was synthesized in analogy to the procedure described inExample 12 using (3R)-3-amino-pyrrolidine-1-carboxylic acid allyl ester(1.28 mmol) and 2,2-[(2-fluoro-4-nitrophenyl)imino]bis-ethanol (40.5mmol).

Yield: 3.38 g, 32%. MW: 378.40, (C18H23FN4O4) MS: 379.5, (M+H)⁺, MethodESI⁺.

(3R)-3-[4-(2-Fluoro-4-nitro-phenyl)-piperazin-1-yl]-pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

To a solution of 3.33 g(3R)-3-[4-(2-fluoro-4-nitro-phenyl)piperazin-1-yl]pyrrolidine-1-carboxylicacid allyl ester (8.8 mmol) in 60 ml THF were added 130 mg of bis(triphenylphosphine)-palladium(II) dichloride (0.088 mmol), 1.0 mlacetic acid (17.6 mmol), and 4.66 ml tributyl tinnhydride (17.6 mmol).The reaction was stirred at rt for 1 h and monitored by TLC. Thesuspension was diluted with 100 ml ether and a pale yellow solidprecipitated. The solid was filtered, washed with ether and hexane anddried. The solid was diluted with 100 ml dichloromethane, 2.30 g BOCanhydride (MW: 218.25, 17.6 mmol) was added and the reaction stirred atRT over night and monitored by TLC. The reaction was diluted withdichloromethane, the org. layer washed with water and brine dried overMg sulfate and filtered. The filtrate was evaporated. The residue waspurified by chromatography, using ethyl acetate as eluent.

Yield: 0.740 g, 21%. MW: 394.44, (C19H27FN4O4) MS: 395.3, (M+H)⁺, MethodESI⁺.

(3R)-3-[4-(4-Benzyloxycarbonylamino-Fluoro-phenyl)-piperazin-1-yl]-pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 19 using 0.780 g(3R)-3-[4-(2-fluoro-4-nitro-phenyl)-piperazin-1-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (1.97 mmol).

Yield: 0.768 g, 78%. MW: 498.6, (C27H35FN4O4) MS: 499.7, (M+H)⁺, MethodESI⁺.

(3R)-3-{4-[2-Fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-piperazin-1-yl}-pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 19 using 0.780 g(3R)-3-[4-(4-benzyloxycarbonylamino-fluoro-phenyl)-piperazin-1-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (1.54 mmol).

Yield: 0.475 g, 66%. MW: 464.54, (C23H33FN4O5) MS: 465.4, (M+H)⁺, MethodESI⁺.

(3R)-3-{4-[4-{(5R)-5-Azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-piperazin-1-yl}-pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 19 using 0.475 g(3R)-3-{4-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-piperazin-1-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (1.02 mmol).

Yield: 0.500 g, quantitative. MW: 489.55, (C23H32FN7O4) MS: 490.4,(M+H)⁺, Method ESI⁺.

(3R)-3-{4-[4-{(5S)-5-Acetylaminomethyl-2-oxo-oxazolidin-3-yl}2-fluoro-phenyl]-piperazin-1-yl}-pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 19 using 0.475 g(3R)-3-{4-[4-{(5R)-5-azidomethyl-2-oxo-oxazolidin-3-yl}2-fluoro-phenyl]-piperazin-1-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (1.02 mmol).

Yield: 0.398 g, 77%. MW: 505.59, (C25H36FN5O5) MS: 506.4, (M+H)⁺, MethodESI⁺.

N-{(5S)-3-[3-Fluoro-4-(4-{(3R)-pyrrolidin-3-yl}-piperazin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

This compound was synthesized in analogy to the procedure described inExample 19 using 0.398 g(3R)-3-{4-[4-{(5S)-5-acetylaminomethyl-2-oxo-oxazolidin-3-yl}2-fluoro-phenyl]-piperazin-1-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.79 mmol).

Yield: 0.398 g, 77%. MW: 405.47, (C20H28FN5O3) MS: 406.8, (M+H)⁺, MethodESI⁺.

7-[(3R)-3-(4-{4[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

This compound was synthesized in analogy to the procedure described inExample 19 using 0.0 90 gN-{(5S)-3-[3-fluoro-4-(4-{(3R)-pyrrolidin-3-yl}-piperazin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide(0.22 mmol) and7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylicacid (0.22 mmol).

Yield: 47 mg, 32 t. MW: 651.68, (C32H35F2N7O6) MS: 652.5, (M+H)⁺; 650.8,(M−H)⁻, Method ESI⁺, ESI⁻.

Example 221-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5R)-5-(methansulfonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

4-{2-Fluoro-4-[(5R)-5-(methansulfonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-carboxylicAcid Tert-Butyl Ester

This compound was synthesized in analogy to the procedure described inExample 9 using4-[4-{(5S)-5-aminomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (1.5 mmol).

Yield: 0.505 g, 71%. MW: 472.53, (C20H29FN4O6S) MS: 473.4, (M+H)⁺;471.7, (M−H)⁻, Method ESI⁺, ESI⁻.

N-[(5R)-3-(3-Fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-methansulfonamide

This compound was synthesized in analogy to the procedure described inExample 19 using 0.5 g4-{2-fluoro-4-[(5R)-5-(methansulfonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-carboxylicacid tert-butyl ester (1.06 mmol.

Yield: 0.39 g, quantitative. MW: 372.42, (C15H21FN4O4S) MS: 373.0,(M+H), Method ESI⁺.

1-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5R)-5-(methan-sulfonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

This compound was synthesized in analogy to the procedure described inExample 10 using 0.082 gN-[(5R)-3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-methansulfonamide(0.22 mmol) and 0.067 g7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylicacid (0.22 mmol).

Yield: 0.079 g, 58%. MW: 618.62, (C27H28F2N6O7S) MS: 619.8, (M+H)⁺;617.7, (M−H)⁻, Method ESI⁺, ESI⁻.

Example 237-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-piperidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

(1-Benzyl-piperidin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine 9.54 g (MW:159.09, 60 mmol) 3,4-difluorobenzene, 11.4 g (60 mmol)4-amino-N-benzylpiperidine and 9.1 66 mmol) triethylamine inacetonitrile were stirred at reflux for 16 h. The solution was dilutedwith EtOAc, washed with water, and brine, dried over MgSO₄ andfiltrated. The filtrate was evaporated, and the crystals wererecrystallized with an ETOAc/hexane mixture.

Yield: 13.5 g, 70%. MW: 329.37, (C18H20FN3O2) MS: 430.1(M+H)⁺, MethodESI⁺.

2-Fluoro-N′-piperidin-4-yl-benzene-1,4-diamine

A mixture of 5 g (15 mmol) of(1-benzyl-piperidin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine in MeOH/EtOAcwith Pd/C 10% was stirred under H2 at RT. The reaction was monitored byTLC. The Pd/C was filtered and the filtrate evaporated to dryness.

Yield: 3.2 g, quant. MW: 209.26, (C11H16FN3) MS: 210.3 (M+H)⁺, MethodESI⁺.

4-(4-Benzyloxycarbonylamino-2-fluoro-phenylamino)-piperidine-1-carboxylicAcid Benzyl Ester

To a mixture of 3.2 g (15 mmol)2-fluoro-N′-piperidin-4-yl-benzene-1,4-diamine in 150 ml acetone, wasadded 75 ml of sat NaHCO₃, and 5.3 ml (37.5 mmol) benzyl chloroformate.It was stirred for 2 h, the acetone was evaporated, and the water layerextracted twice with EtOAc. The organic layer was washed with water andbrine, dried over MgSO₄, filtered and the filtrate evaporated. Theresidue was purified by chromatography using a hex/EtOAc 1:1 mixture.

Yield: 1.5 g, quant. MW: 477.54, (C27H28FN3O4) MS: 478.4 (M+H)⁺, MethodESI⁺.

4-[2-Fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenylamino]-piperidine-1-carboxylicAcid Benzyl Ester

To a solution of 6.6 g (15 mmol)4-(4-benzyloxycarbonylamino-2-fluoro-phenylamino)-piperidine-1-carboxylicacid benzyl ester in 50 ml THF at −78° C. was added dropwise 12.12 mlnBuli 1.6 M (19.5 mmol). The mixture was further stirred at thistemperature for 10 min. The resulting yellow solution was allowed toreach −40° C. over 10 min. 3.0 ml (21 mmol) of (R)-glycidyl butyrate wasthen added and the solution was allowed to reach slowly RT and furtherstirred for 16 h. The reaction was quenched with a saturated ammoniumchloride solution, diluted with 400 ml of EtOAc. The organic layer waswashed with water and brine, dried over MgSO₄, filtered and evaporatedto dryness. The residue was purified by chromatography using aCH₂Cl₂/MeOH 5% mixture.

Yield: 2.58 g, 50%. MW: 443.47, (C23H26FN3O5) MS: 444.6 (M+H)⁺, MethodESI⁺.

4-[4-{(5R)-5-Azidomethyl2-oxo-oxazolidin-3-yl}-2-fluoro-phenylamino]-piperidine-1-carboxylicAcid Benzyl Ester

To a solution of 2.5 g of4-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenylamino]-piperidine-1-carboxylicacid benzyl ester (5.6 mmol) and 1.57 ml (11.2 mmol) triethylamine in 60ml dichloromethane, was added at 0° C. 0.48 ml methanesulfonyl chloride(6.16 mmol). The reaction mixture was allowed to warm up to rt andfurther stirred for 30 min. The reaction was quenched with water, theorganic layer washed with water and brine, dried over Mg sulfate,filtered and the filtrate evaporated.

Yield: 2.88 g, 98%. Ms 522.3 (M+H)⁺, Method ESI⁺.

A suspension of the residue, 717 mg sodium azide (11.04 mmol) and 100 mgtetrabutylammonium iodide (0.27 mmol) in 10 ml DMF was stirred at 80° C.for 20 hrs. The DMF was evaporated, the residue dissolved in ethylacetate, washed with water and brine, the org. layer dried over Mgsulfate, filtered and the filtrate evaporated to dryness.

Yield: 2.5 g, 97%. MW: 468.49, (C23H25FN6O4) MS: 469.7(M+H)⁺, MethodESI⁺.

4-[4-{(5S)-5-Aminomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenylamino]-piperidine-1-carboxylicAcid Benzyl Ester

A solution of 2.51 g (5.35 mmol)4-[4-{(5R)-5-azidomethyl2-oxo-oxazolidin-3-yl}-2-fluoro-phenylamino]-piperidine-1-carboxylicacid benzyl ester, 1.54 g (5.88 mmol) triphenylphosphine and 964 μl(53.5 mmol) water in 30 ml THF was stirred at 50° C. for 16 h.

The THF was evaporated. The residue was purified by chromatography usinga dichloromethane/methanol 9/1 mixture with 1% ammonia.

Yield: 1.44 g, 78%. MW: 442.49, (C23H27FN4O4) MS: 443.6 (M+H)⁺, MethodESI⁺.

4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-piperidine-1-carboxylicAcid Benzyl Ester

A solution of 450 mg4-[4-{(5S)-5-aminomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenylamino]-piperidine-1-carboxylicacid benzyl ester (1.01 mmol), 2 ml acetic acid and 0.093 ml (1 mmol)acetic anhydride was stirred at RT for 1 h. The solvents wereevaporated.

Yield: 484 mg, quant. MW: 484.53, (C25H29FN4O5) MS: 485.7 (M+H)⁺, MethodESI⁺.

N-{(5S)-3-[3-Fluoro-4-(piperidin4-ylamino)-phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide

A suspension of 480 mg (1 mmol)4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-piperidine-1-carboxylicacid benzyl ester and Pd/C in 2 ml of a methanol/acetic acid 1/1 mixturewas stirred under H₂ for 4 h. The Pd/C was filtered and the filtrate wasevaporated to dryness.

Yield: 350 mg, quant. MW: 350.39, (C17H23FN4O3) MS: 351.6 (M+H)⁺, MethodESI⁺.

7-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-piperidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

A suspension of 100 mg N-{(5S)-3-[3-fluoro-4-(piperidin4-ylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide (0.28 mmol),80.66 mg7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (0.28 mmol),0.108 ml trimethylchlorosilane (0.84 mmol) and 0.16 mltriethylamine (1.12 mmol) in 2 ml DMSO was heated under stirring in amicro wave oven at 150° C. for 7 min: The DMSO was evaporated, theresidue was purified by chromatography.

Yield: 54 mg, 31%. MW: 596.60, (C29H30F2N6O6) MS: 597.5 (M+H)⁺, MethodESI⁺.

Known building blocks:

-   3,4-difluorobenzene: 369-34-6, Aldrich 28-836-5-   4-Amino-N-benzylpiperidine: 50541-93-0, Acros 18766-   1,8-Naphthyridine-3-carboxylic acid,    7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-(9Cl):    100361-18-0, Louston International

Example 241-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5S)-5-(methoxythiocarbonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]-naphthyridine-3-carboxylicAcid

1-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5S)-5-(methoxy-thiocarbonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

A mixture of 100 mg {[(5S)-3-[3-fluoro-(1-piperazinyl)phenyl]-2-oxo-5-oxalidinyl]methyl}-carbamothioic acid methyl ester (0.27mmol), 76.71 mg7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (0.27 mmol), 68.65 μl trimethylchlorosilane (0.54 mmol) and 113.49μl triethylamine (0.81 mmol) in 3 ml acetonitrile was stirred in microwave for 8 min at 150° C. The reaction was diluted with water, and theprecipitate was filtered and purified by chromatography using adichloromethane/methanol 9/1 with 1% acetic acid.

Yield: 50 mg, 23%. MW: 614.63, (C28H28F2N6O6S) MS: 615.2 (M+H)⁺, 613.5(M−H)⁻, Method ESI⁺, Method ESI⁻.

Known buiding blocks:

-   Carbamothioic acid, {[(5S)-3-[3-fluoro-(1-piperazinyl)    phenyl]-2-oxo-5-oxalidinyl]methyl}-,o-methyl ester(9cl):    268208-73-7; WO 0027830-   1,8-Naphthyridine-3-carboxylic acid,    7-chloro-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-(9Cl): CAS    100361-18-0, Louston International

Example 251-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-((5)-5-(methylsulfanylthiocarbonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-yl)-4-oxo-1,4dihydro-[1,8]naphthyridine-3-carboxylicAcid

4-{2-Fluoro-4-[(5S)-5-(methylsulfanylthiocarbonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazine-1-carboxylicAcid Tert-Butyl Ester

A mixture of 500 mg 1-piperazinecarboxylic acid,4-[4-[(5S)-5-[(acetylamino)methyl]2-oxo-3-oxazolidinyl]-2-fluoro-phenyl]-1,1-dimethylethylester, (1.26 mmol), 0.152 ml carbon disulfide (2.53 mmol) and 0.176 mltriethylamine (1.26 mmol) in 5 ml THF was stirred at 0° C. for 7 h. 79μl methyliodide (1.26 mmol) was added dropwise to the reaction at 0° C.,and the mixture was stirred at room temperature for 1 h. The mixturediluted with ethyl acetate and the org. layer was washed with water andbrine, dried over Mg sulfate, filtered and the filtrate evaporated.

Yield: 510 mg, 83%. MW: 484.61, (C21H29FN4O4S2) MS: 485.0 (M+H)⁺,)⁻,Method ESI⁺.

[(5S)-3-(3-Fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-dithiocarbamicAcid Methyl Ester

A suspension of 510 mg4-{2-fluoro-4-[(5S)-5-(methyl-sulfanylthiocarbonylamino-methyl)2-oxo-oxazolidin-3-yl]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (1.05 mmol) in 1.25 M/methanol was stirred for 5days. The solvent was evaporated and the residue digested in water. Thewater layer was neutralized at pH 7 with a saturated solution of sodiumbicarbonate and evaporated to dryness The residue was digested inCH₂Cl₂/MeOH. The salts were filtered and the solvent evaporated:

Yield: 250 mg, 25%. MW: 384.49, (C16H21FN4O2S2) MS: 385.5 (M+H)⁺, MethodESI⁺.

1-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-((5S)-5-(methyl-sulfanylthiocarbonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-piperazin-1-yl)-4-oxo-1,4dihydro-[1,8]naphthyridine-3carboxylicAcid

A mixture of 100 mg[(5S)-3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-dithiocarbamicacid methyl ester (0.26 mmol), 73,51 mg7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (0.26 mmol) 108 μl triethylamine. (0.78 mmol) and 65 μltrimethyl-chlorsilane (0.52 mmol), in acetonitrile was stirred in amicro wave oven for 8 min at 150° C. The solution was decanted fromsticky solid, evaporated and the residue digested in water. The solidwas filtered and the purified by chromatography using a 9/1dichloromethane/methanol mixture with 1% acetic acid.

Yield: 50 mg 30%. MW: 630.70, (C28H28F2N6O5S2) MS: 631(M+H)⁺.

Known building blocks:

-   1-piperazinecarboxylic acid,    4-[4-[(5S)-5-[(acetylamino)-methyl]2-oxo-3-oxazolidinyl]-2-fluorophenyl]-,1,1-di-methylethyl    ester, (S)-(9cl): 154990-65-5, U.S. Pat. No. 5,547,950-   1,8-Naphthyridine-3-carboxylic acid,    7-chloro-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-(9Cl):    100361-18-0, Louston International

Example 261-Cyclopropyl-6-fluoro-{4-[2-fluoro-4-{(5S)-2-oxo-5-thioureidomethyl-oxazolidin-3-yl}-phenyl]-piperazin-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

4-[2-Fluoro-4-{(5S)-2-oxo-5-thioureidomethyl-oxazolidin-3-yl}-phenyl]-piperazine-1-carboxylicAcid Tert-Butyl Ester

A suspension of 1 g of4-[2-fluoro-4-[(5R)-5-(isothiocyanatomethyl)-2-oxo-3-oxazolidinyl]phenyl))-1-piperazine-carboxylicacid tert-butyl ester (2.29 mmol) in 5 ml methanol and 5 ml ammoniac 2Nin ethanol was stirred at 0° C. for 3 h. and at RT for 1 h. Theprecipitate was filtered and washed with ether.

Yield: 649 mg, 62%. MW: 453.53, (C20H28FN5O4S) MS: 454 (M+H)⁺, MethodESI⁺.

[(5S)-3-(3-Fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-thiourea

A solution of 649 mg4-[2-fluoro-4-{(5S)-2-oxo-5-thioureidomethyl-oxazolidin-3-yl}-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (1.43 mmol) in a mixture of 6 ml of a 1.25 Msolution of hydrochloric acid in methanol and 1 drop water was stirredfor 4 days. The solvent was evaporated, and the residue was neutralizedat pH 7 with a saturated solution of sodium bicarbonate. The water wasevaporated and the residue was digested in a 95/5dichloromethane/methanol mixture and the solid filtered. The filtratewas purified by chromatography using a 95/5 dichloromethane/methanolmixture with 1% acetic acid.

Yield: 250 mg, 50%. MW: 353.42, (C15H20FN5O2S) MS: 354 (M+H)⁺, MethodESI⁺.

1-Cyclopropyl-6-fluoro-{4-[2-fluoro-4-{(5S)-2-oxo-5-thioureidomethyl-oxazolidin-3-yl}-phenyl]-piperazin-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

A mixture of 100 mg[(5S)-3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-thiourea(0.28 mmol), 87.98 mg7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (0.31 mmol), 71.57 μl trimethylchlorosilane (0.56 mmol) and 118.31μl triethylamine (1.4 mmol) in acetonitrile was stirred in a micro waveoven for 8 min at 150° C. The reaction mixture was diluted with waterand the solid filtered. The solid was purified by chromatography using a95/5 dichloromethane/methanol mixture with 1% acetic acid as eluent toleave 50 mg of an oily residue which was crystallized from aETOAC/hexane mixture.

Yield: 30 mg, 17%. MW: 599.62, (C27H27F2N7O5S) MS: 600 (M+H)⁺, MethodESI⁺.

Known building blocks:

-   1-piperazinecarboxylic acid,    4-[2-fluoro-4-[(5R)-5-(isothiocyanatomethyl)-2-oxo-3-oxazolidinyl]phenyl}-,1,1-dimethylester(9cl):    WO 0027830-   7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic    acid: 100361-18-0,Louston International

Example 277-(4-{4-[5(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxy}-piperidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

A mixture of7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylate(80 mg),(S)-N-[[3-(3-fluoro-4-(4-piperidinyloxy)-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide(described in WO0146164; 100 mg), triethyl-amine (120 μL) andtrimethylchlorsilane (72 μL) in DMSO (2 mL) were stirred at 150° C. for5 minutes (microwave). The solvent was evaporated and the crude reactionwas taken up with water. The resulting solid was filtered andchromatographed over silicagel (dichloromethane/methanol 95:5). Theinteresting fractions were collected and recrystallised from ethylacetate/n hexane affording 70 mg (41%) of colorless material.

C₂₉H₂₉F₂N₅O₇ (597.58)

MS: 598.5 (M+H); 596.4 (M−H).

Example 287-(4-{4-[5(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxy}-piperidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

A mixture of7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylateboron diacetate (described in WO8807998; 175 mg, 0.42mmol(S)-N-[[3-(3-fluoro-4-(4-piperidinyloxy)-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(150 mg, 0.42 mmol) and DABCO (47 mg, 0.42 mmol) were stirred at 150° C.in 2 ml DMSO for 7-minutes (microwave). The solvent was evaporated andthe crude reaction was taken up with water. The resulting solid wasfiltered and chromatographed over silicagel (dichloromethane/methanol95:5). The interesting fractions were collected and crystallised fromacetonitrile affording 23 mg (9%) of colorless material.

C₃₀H₃₀F₂N₄O₇ (596.59)

MS: 597.5 (M+H).

Example 297-(4-{4-[5(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylsulfanyl}-piperidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid

Was prepared in analogy to example 28 starting from7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylateboron diacetateand(S)-N-[[3-(3-fluoro-4-(4-piperidinylsulfanyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.The later being obtained from 4-mercapto-piperidine-1-carboxylic acidtert-butyl ester (J. Antibiotics, 1995, 48, 408-16).

C₃₀H₃₀F₂N₄O₆s (612.66)

MS: 613.8 (M+H)⁺.

Example 307-(4-{4-[5(S)-5(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylsulfanyl}-piperidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicAcid

Was prepared in analogy to example 27 starting from7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylateand(S)-N-[(3-(3-fluoro-4-(4-piperidinylsulfanyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.

C₂₉H₂₉F₂N₅O_(6S) (612.66)

MS: 613.8 (M+H).

All examples were tested against several gram positive and gram negativebacteria. They all have a broader and more pronounced activity than thecorresponding quinolone and oxazolidinone as well as a 1+1 combinationof these two compounds.

Typical MIC range (mg/l)

-   S. aureus (MRSA): 0.125-2 (linezolid 1-2, ciprofloxacin: 0.5-32)-   S. aureus (MSSA): 0.06-1 (linezolid: 1-2, ciprofloxacin: 0.125-1)-   E. faecalis=<0.03-1 (linezolid: 0.5-2, ciprofloxacin: 0.5-32)-   E. faecium=<0.03-1 (linezolid: 1-2), ciprofloxacin: 0.25-32)-   S. pneumoniae=<0.03-1 (linezolid: 0.125-1), ciprofloxacin: 1-4)

To summarize, the compounds, pharmaceutical compositions and products ofthe present invention can be used as antimicrobial, especiallyantibacterial agents.

1. Compounds of Formula (I):

wherein A is a bond, a NH, O, S, SO, SO₂, SO₂NH, PO₄, —NH—CO—NH—,—CO—NH—, —CO—, —CO—O—, —NH—CO—O—, an alkylen group, an alkenylen group,an alkinylen group, a heteroalkylen group, an arylen group, aheteroarylen group, a cycloalkylen group, a heterocycloalkylen group, analkylarylen group or a heteroarylalkylen group or a combination of twoor more of these atoms or groups; X is CR5 or N; Y is CR6 or N; U is For Cl; n is 0, 1, 2 or 3; R1 is H, F, Cl, Br, I, OH, NH₂, an alkyl groupor a heteroalkyl group; R2 is H, F or Cl; R3 is H, an alkyl group, analkenyl group, an alkinyl group, a heteroalkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group, analkylaryl group or a heteroarylalkyl group; R4 is a heteroalkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroarylgroup, an alkylaryl group or a heteroarylalkyl group; R5 is H, F, Cl,OH, NH₂, an alkyl group or a heteroalkyl group, or R3 and R5 can belinked via an alkylen, an alkenylen or a heteroalkylen group or be apart of a cycloalkylen or heterocyclo-alkylen group; in case R3 is no Hand R5 is no H, F, OH, NH₂ or Cl; R6 is H, F, Cl or OMe; or apharmacologically acceptable salt, solvate, hydrate or formulationthereof.
 2. Compounds according to claim 1, wherein R1 is H or NH₂. 3.Compounds according to claims 1 or 2, wherein R2 is H or F.
 4. Compoundsaccording to any one of claims 1 to 3, wherein R3 is an ethyl, a2-propyl, a C3-C6 cycloalkyl, a phenyl or a pyridyl group wherein allthese groups may be substituted by one, two or more flourine atoms oramino groups.
 5. Compounds according to any one of claims 1 to 3,wherein R3 is a cyclopropyl group.
 6. Compounds according to any one ofclaims 1 to 5, wherein R4 is a group of the formula —NHCOCH═CHAryl,—O-Hetero-aryl, —NHSO₂Me, —NHCOOMe, NHCS₂Me, NHCSNH₂, —NHCSOMe or—NHCOMe.
 7. Compounds according to any one of claims 1 to 5, wherein R4is an acetylamino group.
 8. Compounds according to any one of claims 1to 3 or 6 to 7, wherein R3 and R5 together form a bridge of the formula—O—CH₂—N(Me)- or —O—CH₂—CH(Me)-.
 9. Compounds according to any one ofclaims 1 to 7, wherein R5 is H, F, Cl or a methoxy group which may besubstituted by up to three fluorine atoms or a CF₃ group.
 10. Compoundsaccording to any one of claims 1 to 7, wherein X is N or CH. 11.Compounds according to any one of claims 1 to 10, wherein Y is N or CF.12. Compounds according to any one of claims 1 to 11, wherein n is 0.13. Compounds according to any one of claims 1 to 12, wherein A is abond.
 14. Compound according to any one of claims 1 to 12, wherein A isa group of the formula—B₀₋₁D-E₀₋₁_(m)-G₀₋₁-K₀₋₁- wherein the group B is an alkylene, whichmay be substituted by one, two or more fluorine atoms, a —NH— group, ora heteroalkylen group, which may be substituted by one, two or morefluorine atoms and/or at the optionally present nitrogen atoms by analkyl or an acyl group; the groups D independently of each other areoptionally anellated heterocycloalkylen groups with 1, 2, 3 or 4nitrogen atoms, which heterocycloalkylen groups may each be substitutedby one, two or more fluorine atoms and/or which each may be substitutedat one, two, three or four nitrogen atoms by an alkyl or an acyl group;the groups E independently of each other are an alkylene, which may besubstituted by one, two or more fluorine atoms, a —NH— group, or aheteroalkylen group, which may be substituted by one, two or morefluorine atoms and/or at the optionally present nitrogen atoms by analkyl or an acyl group; the groups G independently of each other areoptionally anellated heterocycloalkylen groups with 1, 2, 3 or 4nitrogen atoms, which heterocycloalkylen groups may each be substitutedby one, two or more fluorine atoms and/or which each may be substitutedat one, two, three or four nitrogen atoms by an alkyl or an acyl group;the group K is an alkylene, which may be substituted by one, two or morefluorine atoms, a —NH— group, or a heteroalkylen group, which may besubstituted by one, two or more fluorine atoms and/or at the optionallypresent nitrogen atoms by an alkyl or an acyl group; and m=1, 2, 3 or 4.15. Compound according to any one of claims 1 to 12, wherein A is agroup of the formula—B₀₋₁D-E₀₋₁_(m)-G₀₋₁-K₀₋₁- wherein the group B is an alkylene, whichmay be substituted by one, two or more fluorine atoms, an O, S, SO, SO₂,SO₂NH group, or a heteroalkylen group, which may be substituted by one,two or more fluorine atoms and/or at the optionally present nitrogenatoms by an alkyl or an acyl group; the groups D independently of eachother are optionally anellated heterocycloalkylen groups with 1, 2, 3 or4 nitrogen atoms, which heterocycloalkylen groups may each besubstituted by one, two or more fluorine atoms and/or which each may besubstituted at one, two, three or four nitrogen atoms by an alkyl or anacyl group; the groups E independently of each other are an alkylene,which may be substituted by one, two or more fluorine atoms, an O, S,SO, SO₂, SO₂NH group, or a heteroalkylen group, which may be substitutedby one, two or more fluorine atoms and/or at the optionally presentnitrogen atoms by an alkyl or an acyl group; the groups G independentlyof each other are optionally anellated heterocycloalkylen groups with 1,2, 3 or 4 nitrogen atoms, which heterocycloalkylen groups may each besubstituted by one, two or more fluorine atoms and/or which each may besubstituted at one, two, three or four nitrogen atoms by an alkyl or anacyl group; the group K is an alkylene, which may be substituted by one,two or more fluorine atoms, an O, S, SO, SO₂, SO₂NH group, or aheteroalkylen group, which may be substituted by one, two or morefluorine atoms and/or at the optionally present nitrogen atoms by analkyl or an acyl group; and m=1, 2, 3 or
 4. 16. Compounds according toany one of claims 1 to 12 wherein A is a group of the formula —V—W—,wherein V is a group of the formula O, S, SO, SO₂, SO₂NH, PO₄,—NH—CO—NH—, —CO—NH—, —CO—, —CH₂—, —CO—O—, —(CH₂)₁₋₃—O—, —CH═CH—C(O)—, or—NH—CO—O— and W is a heterocycloalkyl group with 4 to 7 ring atoms or aalkylheterocycloalkyl group with 4 to 7 ring atoms and 1 to 4 carbonatoms in the alkyl chain; all these groups may be substituted by 1, 2, 3or 4 fluorine atoms, methyl or methoxy groups.
 17. Compounds accordingto any one of claims 1 to 12 wherein A is a group of the formula

wherein V is a group of the formula O, S, SO, SO₂, SO₂NH, PO₄,—NH—CO—NH—, —CO—NH—, —CO—, —CH₂—, —CO—O—, —(CH₂)₁₋₃—O—, —CH═CH—C(O)—, or—NH—CO—O—; a is 0, 1, 2, 3 or 4; b is 0, 1, 2, 3 or 4; c is 0, 1, 2, 3or 4 and 1, 2, 3 or 4 hydrogen atoms may be substituted by F, a methyl-or a methoxy group.
 18. Compounds according to claim 16 or 17 wherein Vis O, S, SO or SO₂.
 19. Compounds according to claim 17 wherein V is O;a is 0 or 1; b is 1 or 2 and c is 1 or
 2. 20. Compounds according to anyone of claims 1 to 12 wherein A is a group of the formula

wherein 1, 2, 3 or 4 hydrogen atoms may be substituted by F, a methyl-or a methoxy group.
 21. Compounds according to any one of claims 1 to12, wherein A is selected from the following groups which may besubstituted by one, two or more fluorine atoms or by an alkyl groupwhich may be substituted by one or more fluorine atoms, and wherein theamino groups may be substituted by an alkyl or an acyl group:


22. Compounds according to any one of claims 1 to 21, wherein theabsolute configuration at C-5 of the oxazolidinone ring is (S) accordingto the Cahn-Ingold-Prelog nomenclature system.
 23. Pharmaceuticalcompositions containing a compound according to any one of claims 1 to22 and optionally carriers and/or adjuvants and/or diluents. 24.Pro-drugs, which contain a compound according to any one of claims 1 to22 and at least one pharmacologically acceptable protective group. 25.Use of a compound, a pharmaceutical composition or a prodrug accordingto any one of claims 1 to 18 for the manufacture of medicaments for thetreatment of bacterial infections.